Tl1a patient selection methods, systems, and devices

ABSTRACT

Provided are methods, systems, and kits for selecting a patient for treatment with a therapeutic agent based on a presence of a genotype associated with a positive therapeutic response to the therapeutic agent. The therapeutic agent, in some embodiments, is an inhibitor of TL1A activity or expression, such as for example, an anti-TL1A antibody.

CROSS-REFERENCE

This application claims the benefit of U.S. Patent Application No.62/847,798, filed May 14, 2019, which is hereby incorporated byreference in its entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted electronically in ASCII format and is hereby incorporated byreference in its entirety. Said ASCII copy, created on May 6, 2020, isnamed 56884-761_201_SL.txt and is 14,467,905 bytes in size.

BACKGROUND

Inflammatory disease, fibrostenotic disease, and fibrotic disease pose asignificant health burden worldwide due to the vast number ofindividuals affected and heterogeneous disease pathogenesis and variedclinical manifestations. One such disease is inflammatory bowel disease(IBD), which has two common forms, Crohn's disease (CD) and ulcerativecolitis (UC). IBD is the chronic, relapsing inflammatory disorders ofthe gastrointestinal tract. Incidences of IBD are prevalent, affectingnearly three million individuals in the United States alone.

Few treatment options are available to patients that suffer frominflammatory disease, fibrostenotic disease, and fibrotic disease.Existing anti-inflammatory therapy such as steroids and tumor necrosisfactor (TNF) inhibitors are typically used as a first line treatment fortreating IBD. Unfortunately, a significant number of patients experiencea lack of response or a loss of response to existing anti-inflammatorytherapies, especially TNF inhibitors. While the patient is treated withan anti-inflammatory therapy that is ineffective, the disease worsens.Surgery, in the form of structureplasty (reshaping of the intestine) orresection (removal of the intestine), is the only treatment option forpatients that do not respond to first line therapies. Surgicaltreatments for IBD are invasive, causing post-operative risks for anestimated third of patients undergoing surgery, such as anastomoticleak, infection, and bleeding.

The pathogenesis of inflammatory disease, fibrostenotic disease, andfibrotic disease, like IBD, is thought to involve an uncontrolled immuneresponse that may be triggered by certain environmental factors in agenetically susceptible individual. The heterogeneity of diseasepathogenesis and clinical course, combined with the variable response totreatment and its associated side effects, suggests a personalizedmedicine approach to treating these diseases is the best treatmentstrategy. Yet there are very few personalized therapies available topatients. Accordingly, there is a need to identify targeted therapeuticapproaches for the treatment of inflammatory disease, fibrostenoticdisease, and fibrotic disease and subclinical phenotypes thereof, and aneven greater need to develop reliable methodology to identifyingpatients who, based on their genotype, may respond to any giventherapeutic approach. The needed methodologies would also identifysubjects not yet diagnosed who are at risk of developing the disease,for which preventative interventions could be prescribed to reduce thegrowing health burden.

Genome Wide Association Studies (GWAS) have provided researchers theability to identify genetic variants (e.g., polymorphisms) that aresignificantly associated with IBD and subclinical phenotypes of IBD.GWAS compare the allele frequency in a given population of a particulargenetic variant between unrelated cases and controls, each caserepresenting an affected individual (e.g., patient with IBD) and eachcontrol representing an individual without IBD. GWAS, the Immunochip,and their meta-analysis have enabled the discovery of over 200polymorphisms associated with IBD, including CD and UC.

The first GWAS on IBD identified TNFSF15 as an IBD locus containingseveral polymorphisms associated with IBD. TNFSF15 protein, also knownas TL1A, is a proinflammatory molecule which stimulates proliferationand effector functions of CD8 (+) cytotoxic T cells as well as Th1, Th2,and Th17 cells in the presence of TCR stimulation. TL1A is believed tobe involved in the pathogenesis of IBD by bridging the innate andadaptive immune response, modulating adaptive immunity by augmentingTh1, Th2, and Th17 effector cell function, and T-cell accumulation andimmunopathology of inflamed tissue. Studies have demonstrated thatpatients with IBD who carry certain risk alleles at the TNFSF15 locusshow an increase in TNFSF15 (TL1A) expression and are more likely todevelop severe forms of IBD, as compared to individuals who do not carrythe risk alleles. These findings suggest that inhibiting TL1A expressionand/or activity may be a promising therapeutic strategy in a variety ofT cell-dependent autoimmune diseases, including IBD. These findings alsosuggest that certain TNFSF15 genotypes in patients that confer a risk ofincreased TL1A expression and/or severe forms of disease may proveuseful in the prognosis, diagnosis and treatment of these individuals.

Identifying potential therapeutic targets for the treatment of diseaseand methods of selecting patients for treatment on the basis of GWASalone suffer from significant drawbacks. For example, GWAS relies onlinear polymorphism-polymorphism associations between known risk lociand phenotypic traits, which fail to capture high-dimensional non-linearpolymorphism interactions, such as the types of relationships reflectiveof unknown biology. In addition, individual polymorphisms identifiedusing GWAS often have small effect sizes in a given population. Thus,polymorphisms identified by GWAS are of limited use in predicting asusceptibility to complex diseases, such as IBD (e.g., CD, UC). Further,GWAS fail to convey or account for the biological mechanisms underlyingthe genetic associations between a genetic variant and a phenotypicoutcome (e.g., IBD), rendering them of limited use in identifyingtherapeutic targets.

SUMMARY

Provided herein are genotypes associated with, and therefore predictiveof, a positive therapeutic response of a subject or patient to aninhibitor of TL1A activity or expression (e.g., anti-TL1A antibody) thathave been identified using a machine-learning based approach. Themachine-learning based approach described herein enables theidentification of combinations of polymorphisms with linear andnon-linear interactions that more accurately predict phenotypes ofcomplex disease, such as IBD, as compared to traditional GWAS alone. Thegenotypes described herein are associated with an increase in a level ofTNFSF15 (TL1A) protein expression in a sample obtained from a subject orpatient, as compared to a reference level of TNFSF15 (TL1A) proteinexpression (e.g., derived from a normal individual). The genotypesdisclosed herein are located at gene or genetic loci that are involvedeither directly or indirectly with TL1A-mediated or T-cell dependentinflammatory pathways. In addition, some of the genotypes providedherein are also significantly associated with inflammatory bowel disease(IBD), such as Crohn's disease (CD). The genotypes are useful forselecting a patient or a subject for treatment with an inhibitor of TL1Aactivity or expression. The patient may be diagnosed with IBD, CD, orboth. The subject may be suspected of having IBD, CD, or both.

Non-limiting practical applications of the associations between thegenotypes described herein and incidences of clinical and subclinicalphenotypes in certain populations of individuals are provided herein.For example, some genotypes of the present disclosure can be used topredict a risk that a subject will develop a TL1A-mediated inflammatorydisease, fibrostenotic disease, or a fibrotic disease. The genotypes arealso useful to predict whether a patient diagnosed with some form of aninflammatory, fibrotic or fibrostenotic disease will develop a severeform of the disease, such as a subclinical phenotype thereof.

Further practical applications of the associations between the genotypesdescribed herein include, without limitation, methods, systems, and kitsfor selecting a patient diagnosed with IBD or a subject suspected ofhaving IBD for treatment with an inhibitor of TL1A activity orexpression, provided the patient or the subject is a carrier of thegenotype described herein. In addition, or alternatively, practicalapplications of the associations between the genotypes disclosed hereinand a variation in an expression of TNFSF15 (TL1A) are provided herein.In some cases, the genotypes can be used to identify a patient who maybe suitable for treatment with a targeted TL1A therapy (e.g., a patientcarrying a genotype associated with an increase in TL1A may be suitablefor a treatment with an anti-TL1A therapy). An exemplary conditionincludes Crohn's disease (CD). An exemplary inhibitor of TL1A activityor expression is an anti-TL1A antibody. In some instances, the anti-TL1Aantibody is a neutralizing anti-TL1A antibody.

Aspects disclosed herein provide methods of treating an inflammatory, afibrotic, or a fibrostenotic disease or condition in a subject, themethod comprising administering to the subject a therapeuticallyeffective amount of an inhibitor of Tumor necrosis factor-like cytokine1A (TL1A) activity or expression, provided a presence of at least threepolymorphisms is detected in a sample obtained from the subject, whereinthe at least three polymorphisms are predictive that the subject willtherapeutically respond to the inhibitor of TL1A at a positivepredictive value of at least about 70%. In some embodiments, the atleast three polymorphisms comprises rs1892231, rs56124762, rs6478109,rs2070558, rs2070561, rs11897732, rs6740739, rs17796285, rs7935393,rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976,rs16901748, rs2815844, rs889702, rs2409750, rs1541020, rs4942248,rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376,rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs7935393,rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147,rs2815844, rs889702, rs9806914, rs7278257, or rs11221332, or a proxypolymorphism in linkage disequilibrium therewith as determined with anR² of at least 0.85, or a combination thereof.

In some embodiments, the at least three polymorphisms comprise:rs6478109, rs56124762, and rs1892231; rs6478109, rs56124762, andrs16901748; rs6478109, rs1892231, and rs16901748; rs56124762, rs1892231,and rs16901748; rs6478109, rs2070558, and rs1892231; rs6478109,rs2070558, and rs16901748; rs6478109, rs1892231, and rs16901748;rs2070558, rs1892231, and rs16901748; rs6478109, rs2070561, andrs1892231; rs6478109, rs2070561 and rs16901748; rs6478109, rs1892231,and rs16901748; rs2070561, rs1892231, and rs16901748; rs6478109,rs7935393, and rs1892231; rs6478109, rs7935393, and rs9806914;rs6478109, rs7935393, and rs7278257; rs6478109, rs7935393, andrs2070557; rs6478109, rs1892231, and rs9806914; rs6478109, rs1892231,and rs7278257; rs6478109, rs1892231, and rs2070557; rs6478109,rs9806914, and rs7278257; rs6478109, rs9806914, and rs2070557;rs6478109, rs7278257, and rs2070557; rs7935393, rs1892231, andrs9806914; rs7935393, rs1892231, and rs7278257; rs7935393, rs1892231,and rs2070557; rs7935393, rs9806914, and rs7278257; rs7935393,rs9806914, and rs2070557; rs7935393, rs7278257, and rs2070557;rs1892231, rs9806914, and rs7278257; rs1892231, rs9806914, andrs2070557; rs1892231, rs7278257, and rs2070557; or rs9806914, rs7278257,and rs2070557. In some embodiments, the at least three polymorphismsfurther comprises a fourth polymorphism comprising rs16901748,rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732,rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557,rs4246905, rs10974900, rs12434976, rs2815844, rs889702, rs2409750,rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367,rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279,rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900,rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, orrs11221332, or a proxy polymorphism in linkage disequilibrium therewithas determined with an R² of at least 0.85, or a combination thereof. Insome embodiments, the at least three polymorphisms comprise rs6478109,rs56124762, and rs1892231. In some embodiments, the at least threepolymorphisms comprise rs6478109, rs56124762, and rs16901748. In someembodiments, the at least three polymorphisms comprise rs6478109,rs1892231, and rs16901748. In some embodiments, the at least threepolymorphisms comprise rs56124762, rs1892231, and rs16901748. In someembodiments, the proxy polymorphism in linkage disequilibrium isindependently associated with a clinical phenotype associated with theinflammatory, the fibrotic, or the fibrostenotic disease or condition inthe subject. In some embodiments, the clinical phenotype is structuringand penetrating disease.

In some embodiments, the presence of the at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A at a positive predictive value of at least about 75%.In some embodiments, the presence of the at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A at a positive predictive value of at least about 80%.In some embodiments, the presence of the at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A at a positive predictive value of at least about 85%.In some embodiments, the presence of the at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A at a positive predictive value of at least about 90%.In some embodiments, the presence of the at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A at a positive predictive value of at least about 95%.In some embodiments, the presence of the at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A with a specificity of at least about 70%. In someembodiments, the presence of the at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A with a specificity of at least about 75%. In someembodiments, the presence of the at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A with a specificity of at least about 80%. In someembodiments, the presence of the at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A with a specificity of at least about 85%. In someembodiments, the presence of the at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A with a specificity of at least about 90%. In someembodiments, the presence of the at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A with a specificity of at least about 95%.

In some embodiments, the at least three polymorphisms are detected inthe sample by subjecting the sample to an assay configured to detect apresence of at least three nucleotides corresponding to nucleic acidposition 501 within SEQ ID NOS: 1-41, or 57-59. In some embodiments, theassay comprises polymerase chain reaction (PCR), quantitativereverse-transcription PCR (qPCR), automated sequencing, or genotypearray.

In some embodiments, the inflammatory, fibrotic, or fibrostenoticdisease or condition comprises inflammatory bowel disease, Crohn'sdisease, obstructive Crohn's disease, ulcerative colitis, intestinalfibrosis, intestinal fibrostenosis, rheumatoid arthritis, or primarysclerosing cholangitis. In some embodiments, the Crohn's disease isileal, ileocolonic, or colonic Crohn's disease. In some embodiments, thesubject has, or is at risk for developing, a non-response orloss-of-response to a standard therapy comprising glucocorticosteriods,anti-TNF therapy, anti-a4-b7 therapy, anti-IL12p40 therapy, or acombination thereof. In some embodiments, the inhibitor of TL1A is ananti-TL1A antibody or antigen-binding fragment. In some embodiments, theanti-TL1A antibody binds to the same region of human TL1A as a referenceantibody selected from Table 2B. In some embodiments, methods furthercomprise administering an additional therapeutic agent to the subject.

Aspects disclosed herein provide methods of treating an inflammatory, afibrotic, or a fibrostenotic disease or condition in a subject, themethod comprising administering to the subject a therapeuticallyeffective amount of an inhibitor of Tumor necrosis factor-like cytokine1A (TL1A) activity or expression, provided at least three polymorphismscomprising rs1892231, rs56124762, rs6478109, rs2070558, rs2070561,rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255,rs2070557, rs4246905, rs10974900, rs12434976, rs16901748, rs2815844,rs889702, rs2409750, rs1541020, rs4942248, rs12934476, rs12457255,rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860,rs1528663, rs951279, rs9806914, rs7935393, rs1690492, rs420726,rs7759385, rs10974900, rs1326860, rs2548147, rs2815844, rs889702,rs9806914, rs7278257, or rs11221332, or a proxy polymorphism in linkagedisequilibrium therewith as determined with an R² of at least 0.85, or acombination thereof, are detected in a sample obtained from the subject.

In some embodiments, the at least three polymorphisms comprise:rs6478109, rs56124762, and rs1892231; rs6478109, rs56124762, andrs16901748; rs6478109, rs1892231, and rs16901748; rs56124762, rs1892231,and rs16901748; rs6478109, rs2070558, and rs1892231; rs6478109,rs2070558, and rs16901748; rs6478109, rs1892231, and rs16901748;rs2070558, rs1892231, and rs16901748; rs6478109, rs2070561, andrs1892231; rs6478109, rs2070561, and rs16901748; rs6478109, rs1892231,and rs16901748; rs2070561, rs1892231, and rs16901748; rs6478109,rs7935393, and rs1892231; rs6478109, rs7935393, and rs9806914;rs6478109, rs7935393, and rs7278257; rs6478109, rs7935393, andrs2070557; rs6478109, rs1892231, and rs9806914; rs6478109, rs1892231,and rs7278257; rs6478109, rs1892231, and rs2070557; rs6478109,rs9806914, and rs7278257; rs6478109, rs9806914, and rs2070557;rs6478109, rs7278257, and rs2070557; rs7935393, rs1892231, andrs9806914; rs7935393, rs1892231, and rs7278257; rs7935393, rs1892231,and rs2070557; rs7935393, rs9806914, and rs7278257; rs7935393,rs9806914, and rs2070557; rs7935393, rs7278257, and rs2070557;rs1892231, rs9806914, and rs7278257; rs1892231, rs9806914, andrs2070557; rs1892231, rs7278257, and rs2070557; or rs9806914, rs7278257,and rs2070557. In some embodiments, the at least three polymorphismsfurther comprises a fourth polymorphism comprising rs16901748,rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732,rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557,rs4246905, rs10974900, rs12434976, rs2815844, rs889702, rs2409750,rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367,rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279,rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900,rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, orrs11221332, or a proxy polymorphism in linkage disequilibrium therewithas determined with an R² of at least 0.85, or a combination thereof. Insome embodiments, the at least three polymorphisms comprise rs6478109,rs56124762, and rs1892231. In some embodiments, the at least threepolymorphisms comprise rs6478109, rs56124762, and rs16901748. In someembodiments, the at least three polymorphisms comprise rs6478109,rs1892231, and rs16901748. In some embodiments, the at least threepolymorphisms comprise rs56124762, rs1892231, and rs16901748. In someembodiments, the proxy polymorphism in linkage disequilibrium isindependently associated with a clinical phenotype associated with theinflammatory, the fibrotic, or the fibrostenotic disease or condition inthe subject. In some embodiments, the clinical phenotype is structuringand penetrating disease.

In some embodiments, the presence of the at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A at a positive predictive value of at least about 70%.In some embodiments, the presence of the at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A at a positive predictive value of at least about 75%.In some embodiments, the presence of the at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A at a positive predictive value of at least about 80%.In some embodiments, the presence of the at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A at a positive predictive value of at least about 85%.In some embodiments, the presence of the at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A at a positive predictive value of at least about 90%.In some embodiments, the presence of the at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A at a positive predictive value of at least about 95%.

In some embodiments, the presence of the at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A with a specificity of at least about 70%. In someembodiments, the presence of the at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A with a specificity of at least about 75%. In someembodiments, the presence of the at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A with a specificity of at least about 80%. In someembodiments, the presence of the at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A with a specificity of at least about 85%. In someembodiments, the presence of the at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A with a specificity of at least about 90%. In someembodiments, the presence of the at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A with a specificity of at least about 95%.

In some embodiments, the at least three polymorphisms are detected inthe sample by subjecting the sample to an assay configured to detect apresence of at least three nucleotides corresponding to nucleic acidposition 501 within SEQ ID NOS: 1-41, or 57-59. In some embodiments, theassay comprises polymerase chain reaction (PCR), quantitativereverse-transcription PCR (qPCR), automated sequencing, or genotypearray.

In some embodiments, the inflammatory, fibrotic, or fibrostenoticdisease or condition comprises inflammatory bowel disease, Crohn'sdisease, obstructive Crohn's disease, ulcerative colitis, intestinalfibrosis, intestinal fibrostenosis, rheumatoid arthritis, or primarysclerosing cholangitis. In some embodiments, the Crohn's disease isileal, ileocolonic, or colonic Crohn's disease. In some embodiments, thesubject has, or is at risk for developing, a non-response orloss-of-response to a standard therapy comprising glucocorticosteriods,anti-TNF therapy, anti-a4-b7 therapy, anti-IL12p40 therapy, or acombination thereof. In some embodiments, the inhibitor of TL1A is ananti-TL1A antibody or antigen-binding fragment. In some embodiments, theanti-TL1A antibody binds to the same region of human TL1A as a referenceantibody selected from Table 2B. In some embodiments, methods furthercomprise administering an additional therapeutic agent to the subject.

Aspects disclosed herein provide methods of treating an inflammatory, afibrotic, or a fibrostenotic disease or condition in a subject, themethod comprising: (a) determining whether the subject with aninflammatory, a fibrotic, or a fibrostenotic disease or condition issuitable for treatment with an inhibitor of TL1A activity or expressionby: (i) obtaining or having obtained a sample from the subject; and (ii)subjecting the sample to an assay adapted to detect at least threepolymorphisms that are predictive of the subject exhibiting atherapeutic response to the inhibitor of TL1A activity or expression ata positive predictive value of at least about 70%; and (b) treating thesubject by administering a therapeutically effective amount of theinhibitor of TL1A activity or expression to the subject provided the atleast three polymorphisms are detected. In some embodiments, the atleast three polymorphisms comprise rs1892231, rs56124762, rs6478109,rs2070558, rs2070561, rs11897732, rs6740739, rs17796285, rs7935393,rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976,rs16901748, rs2815844, rs889702, rs2409750, rs1541020, rs4942248,rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376,rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs7935393,rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147,rs2815844, rs889702, rs9806914, rs7278257, rs11221332, or a proxypolymorphism in linkage disequilibrium therewith as determined with anR² of at least 0.85, or a combination thereof.

In some embodiments, the at least three polymorphisms comprise:rs6478109, rs56124762, and rs1892231; rs6478109, rs56124762, andrs16901748; rs6478109, rs1892231, and rs16901748; rs56124762, rs1892231,and rs16901748; rs6478109, rs2070558, and rs1892231; rs6478109,rs2070558, and rs16901748; rs6478109, rs1892231, and rs16901748;rs2070558, rs1892231, and rs16901748; rs6478109, rs2070561, andrs1892231; rs6478109, rs2070561, and rs16901748; rs6478109, rs1892231,and rs16901748; rs2070561, rs1892231, and rs16901748; rs6478109,rs7935393, and rs1892231; rs6478109, rs7935393, and rs9806914;rs6478109, rs7935393, and rs7278257; rs6478109, rs7935393, andrs2070557; rs6478109, rs1892231, and rs9806914; rs6478109, rs1892231,and rs7278257; rs6478109, rs1892231, and rs2070557; rs6478109,rs9806914, and rs7278257; rs6478109, rs9806914, and rs2070557;rs6478109, rs7278257, and rs2070557; rs7935393, rs1892231, andrs9806914; rs7935393, rs1892231, and rs7278257; rs7935393, rs1892231,and rs2070557; rs7935393, rs9806914, and rs7278257; rs7935393,rs9806914, and rs2070557; rs7935393, rs7278257, and rs2070557;rs1892231, rs9806914, and rs7278257; rs1892231, rs9806914, andrs2070557; rs1892231, rs7278257, and rs2070557; or rs9806914, rs7278257,and rs2070557. In some embodiments, the at least three polymorphismsfurther comprises a fourth polymorphism comprising rs16901748,rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732,rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557,rs4246905, rs10974900, rs12434976, rs2815844, rs889702, rs2409750,rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367,rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279,rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900,rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, orrs11221332 or a proxy polymorphism in linkage disequilibrium therewithas determined with an R² of at least 0.85, or a combination thereof. Insome embodiments, the at least three polymorphisms comprise rs6478109,rs56124762, and rs1892231. In some embodiments, the at least threepolymorphisms comprise rs6478109, rs56124762, and rs16901748. In someembodiments, the at least three polymorphisms comprise rs6478109,rs1892231, and rs16901748. In some embodiments, the at least threepolymorphisms comprise rs56124762, rs1892231, and rs16901748.

In some embodiments, the at least three polymorphisms are predictivethat the subject will therapeutically respond to the inhibitor of TL1Aat a positive predictive value of at least about 70%. In someembodiments, the at least three polymorphisms are predictive that thesubject will therapeutically respond to the inhibitor of TL1A at apositive predictive value of at least about 75%. In some embodiments,the at least three polymorphisms are predictive that the subject willtherapeutically respond to the inhibitor of TL1A at a positivepredictive value of at least about 80%. In some embodiments, the atleast three polymorphisms are predictive that the subject willtherapeutically respond to the inhibitor of TL1A at a positivepredictive value of at least about 85%. In some embodiments, the atleast three polymorphisms are predictive that the subject willtherapeutically respond to the inhibitor of TL1A at a positivepredictive value of at least about 90%. In some embodiments, the atleast three polymorphisms are predictive that the subject willtherapeutically respond to the inhibitor of TL1A at a positivepredictive value of at least about 95%.

In some embodiments, the at least three polymorphisms are predictivethat the subject will therapeutically respond to the inhibitor of TL1Awith a specificity of at least about 70%. In some embodiments, the atleast three polymorphisms are predictive that the subject willtherapeutically respond to the inhibitor of TL1A with a specificity ofat least about 75%. In some embodiments, the at least threepolymorphisms are predictive that the subject will therapeuticallyrespond to the inhibitor of TL1A with a specificity of at least about80%. In some embodiments, the at least three polymorphisms arepredictive that the subject will therapeutically respond to theinhibitor of TL1A with a specificity of at least about 85%. In someembodiments, the at least three polymorphisms are predictive that thesubject will therapeutically respond to the inhibitor of TL1A with aspecificity of at least about 90%. In some embodiments, the at leastthree polymorphisms are predictive that the subject will therapeuticallyrespond to the inhibitor of TL1A with a specificity of at least about95%.

In some embodiments, the inflammatory, fibrotic, or fibrostenoticdisease or condition comprises inflammatory bowel disease, Crohn'sdisease, obstructive Crohn's disease, ulcerative colitis, intestinalfibrosis, intestinal fibrostenosis, rheumatoid arthritis, or primarysclerosing cholangitis. In some embodiments, the Crohn's disease isileal, ileocolonic, or colonic Crohn's disease. In some embodiments, thewherein the inhibitor of TL1A activity or expression is an anti-TL1Aantibody or antigen-binding fragment. In some embodiments, the anti-TL1Aantibody binds to the same region of human TL1A as a reference antibodyselected from Table 2B. In some embodiments, methods further compriseadministering an additional therapeutic agent to the subject.

In some embodiments, the subject is at risk of developing a non-responseor loss-of-response to a standard therapy comprisingglucocorticosteriods, anti-TNF therapy, anti-a4-b7 therapy, anti-IL12p40therapy, or a combination thereof. In some embodiments, the proxypolymorphism in linkage disequilibrium is independently associated witha clinical phenotype associated with the inflammatory, the fibrotic, orthe fibrostenotic disease or condition in the subject. In someembodiments, the clinical phenotype is structuring and penetratingdisease.

Aspects disclosed herein provide methods of treating an inflammatory, afibrotic, or a fibrostenotic disease or condition in a subject, themethod comprising: (a) determining whether the subject with aninflammatory, a fibrotic, or a fibrostenotic disease or condition issuitable for treatment with an inhibitor of TL1A activity or expressionby: (i) obtaining or having obtained a sample from the subject; and (ii)subjecting the sample to an assay adapted to detect at least threepolymorphisms comprising rs1892231, rs56124762, rs6478109, rs2070558,rs2070561, rs11897732, rs6740739, rs17796285, rs7935393, rs12934476,rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs16901748,rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs12934476,rs12457255, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456,rs1326860, rs1528663, rs951279, rs9806914, rs7935393, rs1690492,rs420726, rs7759385, rs10974900, rs1326860, rs2548147, rs2815844,rs889702, rs9806914, rs7278257, rs11221332, or a proxy polymorphism inlinkage disequilibrium therewith as determined with an R² of at least0.85, or a combination thereof, and (b) treating the subject byadministering a therapeutically effective amount of the inhibitor ofTL1A activity or expression to the subject.

In some embodiments, the at least three polymorphisms comprise:rs6478109, rs56124762, and rs1892231; rs6478109, rs56124762, andrs16901748; rs6478109, rs1892231, and rs16901748; rs56124762, rs1892231,and rs16901748; rs6478109, rs2070558, and rs1892231; rs6478109,rs2070558, and rs16901748; rs6478109, rs1892231, and rs16901748;rs2070558, rs1892231, and rs16901748; rs6478109, rs2070561, andrs1892231; rs6478109, rs2070561, and rs16901748; rs6478109, rs1892231,and rs16901748; rs2070561, rs1892231, and rs16901748; rs6478109,rs7935393, and rs1892231; rs6478109, rs7935393, and rs9806914;rs6478109, rs7935393, and rs7278257; rs6478109, rs7935393, andrs2070557; rs6478109, rs1892231, and rs9806914; rs6478109, rs1892231,and rs7278257; rs6478109, rs1892231, and rs2070557; rs6478109,rs9806914, and rs7278257; rs6478109, rs9806914, and rs2070557;rs6478109, rs7278257, and rs2070557; rs7935393, rs1892231, andrs9806914; rs7935393, rs1892231, and rs7278257; rs7935393, rs1892231,and rs2070557; rs7935393, rs9806914, and rs7278257; rs7935393,rs9806914, and rs2070557; rs7935393, rs7278257, and rs2070557;rs1892231, rs9806914, and rs7278257; rs1892231, rs9806914, andrs2070557; rs1892231, rs7278257, and rs2070557; or rs9806914, rs7278257,and rs2070557. In some embodiments, the at least three polymorphismsfurther comprises a fourth polymorphism comprising rs16901748,rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732,rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557,rs4246905, rs10974900, rs12434976, rs2815844, rs889702, rs2409750,rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367,rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279,rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900,rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, orrs11221332 or a proxy polymorphism in linkage disequilibrium therewithas determined with an R² of at least 0.85, or a combination thereof. Insome embodiments, the at least three polymorphisms comprise rs6478109,rs56124762, and rs1892231. In some embodiments, the at least threepolymorphisms comprise rs6478109, rs56124762, and rs16901748. In someembodiments, the at least three polymorphisms comprise rs6478109,rs1892231, and rs16901748. In some embodiments, the at least threepolymorphisms comprise rs56124762, rs1892231, and rs16901748.

In some embodiments, the at least three polymorphisms are predictivethat the subject will therapeutically respond to the inhibitor of TL1Aat a positive predictive value of at least about 70%. In someembodiments, the at least three polymorphisms are predictive that thesubject will therapeutically respond to the inhibitor of TL1A at apositive predictive value of at least about 75%. In some embodiments,the at least three polymorphisms are predictive that the subject willtherapeutically respond to the inhibitor of TL1A at a positivepredictive value of at least about 80%. In some embodiments, the atleast three polymorphisms are predictive that the subject willtherapeutically respond to the inhibitor of TL1A at a positivepredictive value of at least about 85%. In some embodiments, the atleast three polymorphisms are predictive that the subject willtherapeutically respond to the inhibitor of TL1A at a positivepredictive value of at least about 90%. In some embodiments, the atleast three polymorphisms are predictive that the subject willtherapeutically respond to the inhibitor of TL1A at a positivepredictive value of at least about 95%.

In some embodiments, the at least three polymorphisms are predictivethat the subject will therapeutically respond to the inhibitor of TL1Awith a specificity of at least about 70%. In some embodiments, the atleast three polymorphisms are predictive that the subject willtherapeutically respond to the inhibitor of TL1A with a specificity ofat least about 75%. In some embodiments, the at least threepolymorphisms are predictive that the subject will therapeuticallyrespond to the inhibitor of TL1A with a specificity of at least about80%. In some embodiments, the at least three polymorphisms arepredictive that the subject will therapeutically respond to theinhibitor of TL1A with a specificity of at least about 85%. In someembodiments, the at least three polymorphisms are predictive that thesubject will therapeutically respond to the inhibitor of TL1A with aspecificity of at least about 90%. In some embodiments, the at leastthree polymorphisms are predictive that the subject will therapeuticallyrespond to the inhibitor of TL1A with a specificity of at least about95%.

In some embodiments, the inflammatory, fibrotic, or fibrostenoticdisease or condition comprises inflammatory bowel disease, Crohn'sdisease, obstructive Crohn's disease, ulcerative colitis, intestinalfibrosis, intestinal fibrostenosis, rheumatoid arthritis, or primarysclerosing cholangitis. In some embodiments, the Crohn's disease isileal, ileocolonic, or colonic Crohn's disease.

In some embodiments, the wherein the inhibitor of TL1A activity orexpression is an anti-TL1A antibody or antigen-binding fragment. In someembodiments, the anti-TL1A antibody binds to the same region of humanTL1A as a reference antibody selected from Table 2B. In someembodiments, methods further comprise administering an additionaltherapeutic agent to the subject.

In some embodiments, the subject is at risk of developing a non-responseor loss-of-response to a standard therapy comprisingglucocorticosteriods, anti-TNF therapy, anti-a4-b7 therapy, anti-IL12p40therapy, or a combination thereof. In some embodiments, the proxypolymorphism in linkage disequilibrium is independently associated witha clinical phenotype associated with the inflammatory, the fibrotic, orthe fibrostenotic disease or condition in the subject. In someembodiments, the clinical phenotype is structuring and penetratingdisease.

Aspects disclosed herein provide methods of treating an inflammatory, afibrotic, or a fibrostenotic disease or condition in a subject, themethod comprising administering to the subject a therapeuticallyeffective amount of an inhibitor of TL1A activity or expression, whereinthe subject expresses at least three polymorphisms comprisingrs16901748, rs6478109, rs56124762, or a proxy polymorphism in linkagedisequilibrium therewith as determined with an R² of at least 0.85. Insome embodiments, the at least three polymorphisms further comprises afourth polymorphism comprising rs16901748, rs1892231, rs56124762,rs6478109, rs2070558, rs2070561, rs11897732, rs6740739, rs17796285,rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900,rs12434976, rs2815844, rs889702, rs2409750, rs1541020, rs4942248,rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376,rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs7935393,rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147,rs2815844, rs889702, rs9806914, rs7278257, or rs11221332 or a proxypolymorphism in linkage disequilibrium therewith as determined with anR² of at least 0.85, or a combination thereof. In some embodiments, theat least three polymorphisms are predictive that the subject willtherapeutically respond to the inhibitor of TL1A at a positivepredictive value of at least about 70%. In some embodiments, the atleast three polymorphisms are predictive that the subject willtherapeutically respond to the inhibitor of TL1A at a positivepredictive value of at least about 75%. In some embodiments, the atleast three polymorphisms are predictive that the subject willtherapeutically respond to the inhibitor of TL1A at a positivepredictive value of at least about 80%. In some embodiments, the atleast three polymorphisms are predictive that the subject willtherapeutically respond to the inhibitor of TL1A at a positivepredictive value of at least about 85%. In some embodiments, the atleast three polymorphisms are predictive that the subject willtherapeutically respond to the inhibitor of TL1A at a positivepredictive value of at least about 90%. In some embodiments, the atleast three polymorphisms are predictive that the subject willtherapeutically respond to the inhibitor of TL1A at a positivepredictive value of at least about 95%. In some embodiments, the atleast three polymorphisms are predictive that the subject willtherapeutically respond to the inhibitor of TL1A with a specificity ofat least about 70%. In some embodiments, the at least threepolymorphisms are predictive that the subject will therapeuticallyrespond to the inhibitor of TL1A with a specificity of at least about75%. In some embodiments, the at least three polymorphisms arepredictive that the subject will therapeutically respond to theinhibitor of TL1A with a specificity of at least about 80%. In someembodiments, the at least three polymorphisms are predictive that thesubject will therapeutically respond to the inhibitor of TL1A with aspecificity of at least about 85%. In some embodiments, the at leastthree polymorphisms are predictive that the subject will therapeuticallyrespond to the inhibitor of TL1A with a specificity of at least about90%. In some embodiments, the at least three polymorphisms arepredictive that the subject will therapeutically respond to theinhibitor of TL1A with a specificity of at least about 95%.=In someembodiments, the inflammatory, fibrotic, or fibrostenotic disease orcondition comprises inflammatory bowel disease, Crohn's disease,obstructive Crohn's disease, ulcerative colitis, intestinal fibrosis,intestinal fibrostenosis, rheumatoid arthritis, or primary sclerosingcholangitis. In some embodiments, the Crohn's disease is ileal,ileocolonic, or colonic Crohn's disease. In some embodiments, thewherein the inhibitor of TL1A activity or expression is an anti-TL1Aantibody or antigen-binding fragment. In some embodiments, the anti-TL1Aantibody binds to the same region of human TL1A as a reference antibodyselected from Table 2B. In some embodiments, methods further compriseadministering an additional therapeutic agent to the subject. In someembodiments, the subject is at risk of developing a non-response orloss-of-response to a standard therapy comprising glucocorticosteriods,anti-TNF therapy, anti-a4-b7 therapy, anti-IL12p40 therapy, or acombination thereof. In some embodiments, the proxy polymorphism inlinkage disequilibrium is independently associated with a clinicalphenotype associated with the inflammatory, the fibrotic, or thefibrostenotic disease or condition in the subject. In some embodiments,the clinical phenotype is structuring and penetrating disease.

Aspects disclosed herein provide methods comprising: (a) providing asample obtained from a subject with an inflammatory, a fibrotic, or afibrostenotic disease or condition; and (b) detecting a presence of atleast three polymorphisms in the sample with a genotyping assay, whereinthe presence of the at least three polymorphisms is predictive of atherapeutic response in the subject to a treatment with an inhibitor ofTL1A activity or expression at a positive predictive value of at leastabout 70%. In some embodiments, the at least three polymorphismscomprise rs1892231, rs56124762, rs6478109, rs2070558, rs2070561,rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255,rs2070557, rs4246905, rs10974900, rs12434976, rs16901748, rs2815844,rs889702, rs2409750, rs1541020, rs4942248, rs12934476, rs12457255,rs2297437, rs41309367, rs10733509, rs10750376, rs10932456, rs1326860,rs1528663, rs951279, rs9806914, rs7935393, rs1690492, rs420726,rs7759385, rs10974900, rs1326860, rs2548147, rs2815844, rs889702,rs9806914, rs7278257, rs11221332, or a proxy polymorphism in linkagedisequilibrium therewith as determined with an R² of at least 0.85, or acombination thereof.

In some embodiments, detecting the at least three polymorphismscomprises detecting at least three genotypes corresponding to nucleicacid position 501 within at least three of SEQ ID NOS: 1-41, or 57-59.In some embodiments, the presence of at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A at a positive predictive value of at least about 75%.In some embodiments, the presence of at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A at a positive predictive value of at least about 80%.In some embodiments, the presence of at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A at a positive predictive value of at least about 85%.In some embodiments, the presence of at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A at a positive predictive value of at least about 90%.In some embodiments, the presence of at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A at a positive predictive value of at least about 95%.

In some embodiments, the presence of at least three polymorphisms ispredictive that the subject will therapeutically respond to theinhibitor of TL1A with a specificity of at least about 70%. In someembodiments, the presence of at least three polymorphisms is predictivethat the subject will therapeutically respond to the inhibitor of TL1Awith a specificity of at least about 75%. In some embodiments, thepresence of at least three polymorphisms is predictive that the subjectwill therapeutically respond to the inhibitor of TL1A with a specificityof at least about 80%. In some embodiments, the presence of at leastthree polymorphisms is predictive that the subject will therapeuticallyrespond to the inhibitor of TL1A with a specificity of at least about85%. In some embodiments, the presence of at least three polymorphismsis predictive that the subject will therapeutically respond to theinhibitor of TL1A with a specificity of at least about 90%. In someembodiments, the presence of at least three polymorphisms is predictivethat the subject will therapeutically respond to the inhibitor of TL1Awith a specificity of at least about 95%.

In some embodiments, methods further comprise administering to thesubject a therapeutically effective amount of the inhibitor of TL1Aactivity or expression to treat the inflammatory, fibrotic, orfibrostenotic disease or condition. In some embodiments, the subject isat risk of developing a non-response or loss-of-response to a standardtherapy comprising glucocorticosteriods, anti-TNF therapy, anti-a4-b7therapy, anti-IL12p40 therapy, or a combination thereof. In someembodiments, the inflammatory, fibrotic, or fibrostenotic disease orcondition comprises inflammatory bowel disease, Crohn's disease,obstructive Crohn's disease, ulcerative colitis, intestinal fibrosis,intestinal fibrostenosis, rheumatoid arthritis, or primary sclerosingcholangitis. In some embodiments, the Crohn's disease is ileal,ileocolonic, or colonic Crohn's disease.

In some embodiments, the wherein the inhibitor of TL1A activity orexpression is an anti-TL1A antibody or antigen-binding fragment. In someembodiments, the anti-TL1A antibody binds to the same region of humanTL1A as a reference antibody selected from Table 2B. In someembodiments, methods further comprise administering an additionaltherapeutic agent to the subject.

In some embodiments, the at least three polymorphisms comprise:rs6478109, rs56124762, and rs1892231; rs6478109, rs56124762, andrs16901748; rs6478109, rs1892231, and rs16901748; rs56124762, rs1892231,and rs16901748; rs6478109, rs2070558, and rs1892231; rs6478109,rs2070558, and rs16901748; rs6478109, rs1892231, and rs16901748;rs207558, rs1892231, and rs16901748; rs6478109, rs2070561, andrs1892231; rs6478109, rs2070561, and rs16901748; rs6478109, rs1892231,and rs16901748; rs2070561, rs1892231, and rs16901748; rs6478109,rs7935393, and rs1892231; rs6478109, rs7935393, and rs9806914;rs6478109, rs7935393, and rs7278257; rs6478109, rs7935393, andrs2070557; rs6478109, rs1892231, and rs9806914; rs6478109, rs1892231,and rs7278257; rs6478109, rs1892231, and rs207557; rs6478109, rs9806914,and rs7278257; rs6478109, rs9806914, and rs2070557; rs6478109,rs7278257, and rs2070557; rs7935393, rs1892231, and rs9806914;rs7935393, rs1892231, and rs7278257; rs7935393, rs1892231, andrs2070557; rs7935393, rs9806914, and rs7278257; rs7935393, rs9806914,and rs2070557; rs7935393, rs7278257, and rs2070557; rs1892231,rs9806914, and rs7278257; rs1892231, rs9806914, and rs2070557;rs1892231, rs7278257, and rs2070557; or rs9806914, rs7278257, andrs2070557. In some embodiments, the at least three polymorphisms furthercomprises a fourth polymorphism comprising rs16901748, rs1892231,rs56124762, rs6478109, rs2070558, rs2070561, rs11897732, rs6740739,rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905,rs10974900, rs12434976, rs2815844, rs889702, rs2409750, rs1541020,rs4942248, rs12934476, rs12457255, rs2297437, rs41309367, rs10733509,rs10750376, rs10932456, rs1326860, rs1528663, rs951279, rs9806914,rs7935393, rs1690492, rs420726, rs7759385, rs10974900, rs1326860,rs2548147, rs2815844, rs889702, rs9806914, rs7278257, or rs11221332, ora combination thereof. In some embodiments, the at least threepolymorphisms comprise rs6478109, rs56124762, and rs1892231. In someembodiments, the at least three polymorphisms comprise rs6478109,rs56124762, and rs16901748. In some embodiments, the at least threepolymorphisms comprise rs6478109, rs1892231, and rs16901748. In someembodiments, the at least three polymorphisms comprise rs56124762,rs1892231, and rs16901748. In some embodiments, the proxy polymorphismin linkage disequilibrium is independently associated with a clinicalphenotype associated with the inflammatory, the fibrotic, or thefibrostenotic disease or condition in the subject. In some embodiments,the clinical phenotype is structuring and penetrating disease.

Aspects disclosed herein provide methods comprising: (a) providing asample obtained from a subject with an inflammatory, a fibrotic, or afibrostenotic disease or condition; and (b) detecting a presence of atleast three polymorphisms in the sample with a genotyping assay, said atleast three polymorphisms comprising rs1892231, rs56124762, rs6478109,rs2070558, rs2070561, rs11897732, rs6740739, rs17796285, rs7935393,rs12934476, rs12457255, rs2070557, rs4246905, rs10974900, rs12434976,rs16901748, rs2815844, rs889702, rs2409750, rs1541020, rs4942248,rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376,rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs7935393,rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147,rs2815844, rs889702, rs9806914, rs7278257, rs11221332, or a proxypolymorphism in linkage disequilibrium therewith as determined with anR² of at least 0.85, or a combination thereof.

In some embodiments, detecting the at least three polymorphismscomprises detecting at least three genotypes corresponding to nucleicacid position 501 within at least three of SEQ ID NOS: 1-41, or 57-59.In some embodiments, the presence of at least three polymorphisms ispredictive of a therapeutic response in a subject to a treatment withthe inhibitor of TL1A at a positive predictive value of at least about70%. In some embodiments, the presence of at least three polymorphismsis predictive of a therapeutic response in a subject to a treatment withthe inhibitor of TL1A at a positive predictive value of at least about75%. In some embodiments, the presence of at least three polymorphismsis predictive of a therapeutic response in a subject to a treatment withthe inhibitor of TL1A at a positive predictive value of at least about80%. In some embodiments, the presence of at least three polymorphismsis predictive of a therapeutic response in a subject to a treatment withthe inhibitor of TL1A at a positive predictive value of at least about85%. In some embodiments, the presence of at least three polymorphismsis predictive of a therapeutic response in a subject to a treatment withthe inhibitor of TL1A at a positive predictive value of at least about90%. In some embodiments, the presence of at least three polymorphismsis predictive of a therapeutic response in a subject to a treatment withthe inhibitor of TL1A at a positive predictive value of at least about95%.

In some embodiments, the presence of at least three polymorphisms ispredictive of a therapeutic response in a subject to a treatment withthe inhibitor of TL1A with a specificity of at least about 70%. In someembodiments, the presence of at least three polymorphisms is predictiveof a therapeutic response in a subject to a treatment with the inhibitorof TL1A with a specificity of at least about 75%. In some embodiments,the presence of at least three polymorphisms is predictive of atherapeutic response in a subject to a treatment with the inhibitor ofTL1A with a specificity of at least about 80%. In some embodiments, thepresence of at least three polymorphisms is predictive of a therapeuticresponse in a subject to a treatment with the inhibitor of TL1A with aspecificity of at least about 85%. In some embodiments, the presence ofat least three polymorphisms is predictive of a therapeutic response ina subject to a treatment with the inhibitor of TL1A with a specificityof at least about 90%. In some embodiments, the presence of at leastthree polymorphisms is predictive of a therapeutic response in a subjectto a treatment with the inhibitor of TL1A with a specificity of at leastabout 95%.

In some embodiments, methods further comprise administering to thesubject a therapeutically effective amount of the inhibitor of TL1Aactivity or expression to treat the inflammatory, fibrotic, orfibrostenotic disease or condition. In some embodiments, the subject isat risk of developing a non-response or loss-of-response to a standardtherapy comprising glucocorticosteriods, anti-TNF therapy, anti-a4-b7therapy, anti-IL12p40 therapy, or a combination thereof. In someembodiments, the inflammatory, fibrotic, or fibrostenotic disease orcondition comprises inflammatory bowel disease, Crohn's disease,obstructive Crohn's disease, ulcerative colitis, intestinal fibrosis,intestinal fibrostenosis, rheumatoid arthritis, or primary sclerosingcholangitis. In some embodiments, the Crohn's disease is ileal,ileocolonic, or colonic Crohn's disease.

In some embodiments, the wherein the inhibitor of TL1A activity orexpression is an anti-TL1A antibody or antigen-binding fragment. In someembodiments, the anti-TL1A antibody binds to the same region of humanTL1A as a reference antibody selected from Table 2B. In someembodiments, methods further comprise administering an additionaltherapeutic agent to the subject.

In some embodiments, the at least three polymorphisms comprise:rs6478109, rs56124762, and rs1892231; rs6478109, rs56124762, andrs16901748; rs6478109, rs1892231, and rs16901748; rs56124762, rs1892231,and rs16901748; rs6478109, rs2070558, and rs1892231; rs6478109,rs2070558, and rs16901748; rs6478109, rs1892231, and rs16901748;rs207558, rs1892231, and rs16901748; rs6478109, rs2070561, andrs1892231; rs6478109, rs2070561, and rs16901748; rs6478109, rs1892231,and rs16901748; rs2070561, rs1892231, and rs16901748; rs6478109,rs7935393, and rs1892231; rs6478109, rs7935393, and rs9806914;rs6478109, rs7935393, and rs7278257; rs6478109, rs7935393, andrs2070557; rs6478109, rs1892231, and rs9806914; rs6478109, rs1892231,and rs7278257; rs6478109, rs1892231, and rs207557; rs6478109, rs9806914,and rs7278257; rs6478109, rs9806914, and rs207557; rs6478109, rs7278257,and rs2070557; rs7935393, rs1892231, and rs9806914; rs7935393,rs1892231, and rs7278257; rs7935393, rs1892231, and rs2070557;rs7935393, rs9806914, and rs7278257; rs7935393, rs9806914, andrs2070557; rs7935393, rs7278257, and rs2070557; rs1892231, rs9806914,and rs7278257; rs1892231, rs9806914, and rs2070557; rs1892231,rs7278257, and rs2070557; or rs9806914, rs7278257, and rs2070557. Insome embodiments, the at least three polymorphisms further comprises afourth polymorphism comprising rs16901748, rs1892231, rs56124762,rs6478109, rs2070558, rs2070561, rs11897732, rs6740739, rs17796285,rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900,rs12434976, rs2815844, rs889702, rs2409750, rs1541020, rs4942248,rs12934476, rs12457255, rs2297437, rs41309367, rs10733509, rs10750376,rs10932456, rs1326860, rs1528663, rs951279, rs9806914, rs7935393,rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147,rs2815844, rs889702, rs9806914, rs7278257, or rs11221332, or acombination thereof. In some embodiments, the at least threepolymorphisms comprise rs6478109, rs56124762, and rs1892231. In someembodiments, the at least three polymorphisms comprise rs6478109,rs56124762, and rs16901748. In some embodiments, the at least threepolymorphisms comprise rs6478109, rs1892231, and rs16901748. In someembodiments, the at least three polymorphisms comprise rs56124762,rs1892231, and rs16901748. In some embodiments, the proxy polymorphismin linkage disequilibrium is independently associated with a clinicalphenotype associated with the inflammatory, the fibrotic, or thefibrostenotic disease or condition in the subject. In some embodiments,the clinical phenotype is structuring and penetrating disease.

Aspects disclosed herein provide computer-implemented methodscomprising: (a) receiving genotype data of a subject with aninflammatory, a fibrotic, or a fibrostenotic disease or condition; and(b) analyzing the genotype data to detect a presence of at least threegenotypes predictive of a therapeutic response in the subject to atreatment with an inhibitor of Tumor necrosis factor-like cytokine 1A(TL1A) activity or expression to treat the inflammatory, the fibrotic,or the fibrostenotic disease or condition with a positive predictivevalue of at least about 70%. In some embodiments, the at least threegenotypes comprise at least three polymorphisms comprising rs1892231,rs56124762, rs6478109, rs2070558, rs2070561, rs11897732, rs6740739,rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905,rs10974900, rs12434976, rs16901748, rs2815844, rs889702, rs2409750,rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367,rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279,rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900,rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, orrs11221332, or a proxy polymorphism in linkage disequilibrium therewithas determined with an R² of at least 0.85, or a combination thereof.

In some embodiments, methods further comprise generating a TNFSF15profile comprising a positive, a negative, or an indeterminant resultfor a therapeutic response to a treatment with the inhibitor of TL1Aactivity or expression.

In some embodiments, determining the likelihood that the subject willtherapeutically respond to the treatment with the inhibitor of TL1Aactivity or expression is performed at a positive predictive value of atleast about 70%. In some embodiments, determining the likelihood thatthe subject will therapeutically respond to the treatment with theinhibitor of TL1A activity or expression is performed at a positivepredictive value of at least about 75%. In some embodiments, determiningthe likelihood that the subject will therapeutically respond to thetreatment with the inhibitor of TL1A activity or expression is performedat a positive predictive value of at least about 80%. In someembodiments, determining the likelihood that the subject willtherapeutically respond to the treatment with the inhibitor of TL1Aactivity or expression is performed at a positive predictive value of atleast about 85%. In some embodiments, determining the likelihood thatthe subject will therapeutically respond to the treatment with theinhibitor of TL1A activity or expression is performed at a positivepredictive value of at least about 90%. In some embodiments, determiningthe likelihood that the subject will therapeutically respond to thetreatment with the inhibitor of TL1A activity or expression is performedat a positive predictive value of at least about 95%.

In some embodiments, determining the likelihood that the subject willtherapeutically respond to the treatment with the inhibitor of TL1Aactivity or expression is performed at with a specificity of at leastabout 70%. In some embodiments, determining the likelihood that thesubject will therapeutically respond to the treatment with the inhibitorof TL1A activity or expression is performed at with a specificity of atleast about 75%. In some embodiments, determining the likelihood thatthe subject will therapeutically respond to the treatment with theinhibitor of TL1A activity or expression is performed at with aspecificity of at least about 80%. In some embodiments, determining thelikelihood that the subject will therapeutically respond to thetreatment with the inhibitor of TL1A activity or expression is performedat with a specificity of at least about 85%. In some embodiments,determining the likelihood that the subject will therapeutically respondto the treatment with the inhibitor of TL1A activity or expression isperformed at with a specificity of at least about 90%. In someembodiments, determining the likelihood that the subject willtherapeutically respond to the treatment with the inhibitor of TL1Aactivity or expression is performed at with a specificity of at leastabout 95%.

In some embodiments, the at least three polymorphisms comprise:rs6478109, rs56124762, and rs1892231; rs6478109, rs56124762, andrs16901748; rs6478109, rs1892231, and rs16901748; rs56124762, rs1892231,and rs16901748; rs6478109, rs2070558, and rs1892231; rs6478109,rs2070558, and rs16901748; rs6478109, rs1892231, and rs16901748;rs2070558, rs1892231, and rs16901748; rs6478109, rs2070561, andrs1892231; rs6478109, rs2070561, and rs16901748; rs6478109, rs1892231,and rs16901748; rs2070561, rs1892231, and rs16901748; rs6478109,rs7935393, and rs1892231; rs6478109, rs7935393, and rs9806914;rs6478109, rs7935393, and rs7278257; rs6478109, rs7935393, andrs2070557; rs6478109, rs1892231, and rs9806914; rs6478109, rs1892231,and rs7278257; rs6478109, rs1892231, and rs2070557; rs6478109,rs9806914, and rs7278257; rs6478109, rs9806914, and rs2070557;rs6478109, rs7278257, and rs2070557; rs7935393, rs1892231, andrs9806914; rs7935393, rs1892231, and rs7278257; rs7935393, rs1892231,and rs2070557; rs7935393, rs9806914, and rs7278257; rs7935393,rs9806914, and rs2070557; rs7935393, rs7278257, and rs2070557;rs1892231, rs9806914, and rs7278257; rs1892231, rs9806914, andrs2070557; rs1892231, rs7278257, and rs2070557; or rs9806914, rs7278257,and rs2070557. In some embodiments, the at least three polymorphismsfurther comprises a fourth polymorphism comprising rs16901748,rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732,rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557,rs4246905, rs10974900, rs12434976, rs2815844, rs889702, rs2409750,rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367,rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279,rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900,rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, orrs11221332, or a proxy polymorphism in linkage disequilibrium therewithas determined with an R² of at least 0.85, or a combination thereof. Insome embodiments, the at least three polymorphisms comprise rs6478109,rs56124762, and rs1892231. In some embodiments, the at least threepolymorphisms comprise rs6478109, rs56124762, and rs16901748. In someembodiments, the at least three polymorphisms comprise rs6478109,rs1892231, and rs16901748. In some embodiments, the at least threepolymorphisms comprise rs56124762, rs1892231, and rs16901748.

In some embodiments, methods further comprise generating a reportcomprising the TNFSF15 profile for display to a user. In someembodiments, the inflammatory, the fibrotic, and the fibrostenoticdisease or condition comprises inflammatory bowel disease, Crohn'sdisease, obstructive Crohn's disease, ulcerative colitis, intestinalfibrosis, intestinal fibrostenosis, rheumatoid arthritis, or primarysclerosing cholangitis. In some embodiments, the Crohn's disease isileal, ileocolonic, or colonic Crohn's disease. In some embodiments, theinhibitor of TL1A activity or expression is an anti-TL1A antibody orantigen-binding fragment. In some embodiments, the anti-TL1A antibodybinds to the same region of human TL1A as a reference antibody selectedfrom Table 2B. In some embodiments, the proxy polymorphism in linkagedisequilibrium is independently associated with a clinical phenotypeassociated with the inflammatory, the fibrotic, or the fibrostenoticdisease or condition in the subject. In some embodiments, the clinicalphenotype is structuring and penetrating disease.

Aspects disclosed herein provide kits comprising: (a) at least threeprimer pairs, each primer pair comprising a first primer and a secondprimer, where said first primer comprises at least 10 contiguous nucleicacids corresponding to nucleotides 4090-500 of SEQ ID NOS: 1-41, or57-59, and wherein said second primer comprises at least 10 contiguousnucleic acids corresponding to nucleotides 4090-500 of a reversecomplement to SEQ ID NOS: 1-41, or 57-59; and (b) at least threepolynucleotide molecules, each polynucleotide molecule comprising adetectable moiety, wherein the polynucleotide molecule comprises anucleic acid sequence comprising a nucleotide corresponding tonucleotide position 501 of SEQ ID NOS: 1-41, or 57-59. In someembodiments, the kit is useful for selecting a patient with aninflammatory, a fibrotic, or a fibrostenotic disease or condition fortreatment with an inhibitor of TL1A activity or expression, provided thepresence of the at least three polymorphisms is detected in a sampleobtained from the patient.

Aspects disclosed herein provide kits comprising: (a) a first primerpair comprising a first forward primer provided in any one of SEQ IDNOS: 364101-364110 and a corresponding first reverse primer provided inSEQ ID NO: in any one of SEQ ID NOS: 364111-364120; (b) a second primerpair comprising a second forward primer provided in any one of SEQ IDNOS: 364101-364110 and a corresponding second reverse primer provided inany one of SEQ ID NOS: 364111-364120; (c) a third primer pair comprisinga third forward primer provided in any one of SEQ ID NOS: 364101-364110and a corresponding third reverse primer provided in any one of SEQ IDNOS: 364111-364120, wherein the first primer pair, the second primerpair, and the third primer pair are not the same; and (d) at least threepolynucleotide molecules, each polynucleotide molecule comprising adetectable moiety, wherein the polynucleotide molecule comprises anucleic acid sequence comprising a nucleotide corresponding tonucleotide position 501 of SEQ ID NOS: 1-41, or 57-59. In someembodiments, the kit is useful for selecting a patient with aninflammatory, a fibrotic, or a fibrostenotic disease or condition fortreatment with an inhibitor of TL1A activity or expression, provided thepresence of the at least three polymorphisms is detected in a sampleobtained from the patient.

Aspects disclosed herein provide methods of selecting a patient with aninflammatory, a fibrotic, or a fibrostenotic disease or condition fortreatment with an inhibitor of TL1A activity or expression, the methodcomprising: (a) assaying a sample obtained from the subject using thekit of the present disclosure; (b) detecting at least three genotypes inthe sample; and (c) selecting the patient for treatment with aninhibitor of TL1A activity or expression to treat an inflammatory, afibrotic, or a fibrostenotic disease or condition in the subject. Insome embodiments, methods further comprise administering the inhibitorof TL1A activity or expression to the patient to treat the inflammatory,the fibrotic, or the fibrostenotic disease or condition in the subject.

Aspects of the present disclosure provide a non-transitory computerreadable medium comprising machine executable code that, upon executionby one or more computer processors, implements any of the methods aboveor elsewhere herein.

Aspects of the present disclosure provide a system comprising one ormore computer processors and computer memory coupled thereto. Thecomputer memory comprises machine executable code that, upon executionby the one or more computer processors, implements any of the methodsabove or elsewhere herein.

Aspects provided herein provide methods of treating at least one of aninflammatory, a fibrotic, and a fibrostenotic disease or condition in asubject, the method comprising administering to the subject atherapeutically effective amount of an inhibitor of TL1A activity orexpression, provided a presence of a genotype is detected in a sampleobtained from the subject, the genotype comprising at least threepolymorphisms provided in Table 1. In some embodiments, the at leastthree polymorphisms is selected from the group consisting of rs11897732,rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557,rs4246905, rs10974900, rs12434976, rs16901748, rs2815844, rs889702,rs2409750, rs1541020, rs4942248, rs12934476, rs12457255, rs2297437,rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663,rs1892231, rs951279, rs9806914, rs7935393, rs1690492, rs420726,rs7759385, rs10974900, rs1326860, rs2548147, rs2815844, rs889702,rs9806914, rs6478109, rs7278257, and rs11221332. In some embodiments,the at least three polymorphisms are selected from the group consistingof a “G” allele at rs11897732, an “A” allele at rs6740739, a “G” alleleat rs17796285, an “A” allele at rs7935393, a “G” allele at rs12934476,an “A” allele at rs12457255, an “A” allele at rs2070557, an “A” alleleat rs4246905, an “A” allele at rs10974900, a “C” allele at rs12434976,an “A” allele at rs16901748, an “A” allele at rs2815844, a “G” allele atrs889702, a “C” allele at rs2409750, an “A” allele at rs1541020, a “T”allele at rs4942248, a “G” allele at rs12934476, an “A” allele atrs12457255, an “A” allele at rs2297437, a “G” allele at rs41309367, an“A” allele at rs10733509, a “G” allele at rs10750376, a “G” allele atrs10932456, an “A” allele at rs1326860, a “G” allele at rs1528663, a “C”allele at rs1892231, an “A” allele at rs951279, an “A” allele atrs9806914, an “A” allele at rs7935393, a “G” allele at rs1690492, an “A”allele at rs420726, a “T” allele at rs7759385, an “A” allele atrs10974900, an “A” allele at rs1326860, a “C” allele at rs2548147, an“A” allele at rs2815844, a “G” allele at rs889702, an “A” allele atrs9806914, an “A” allele at rs6478109, a “C” allele at rs7278257, and an“A” allele at rs11221332. In some embodiments, a polymorphism of the atleast three polymorphisms comprises a minor allele provided in Table 1.In some embodiments, a polymorphism of the at least three polymorphismscomprises a major allele provided in Table 1. In some embodiments, thegenotype is heterozygous. In some embodiments, the genotype ishomozygous. In some embodiments, the at least three polymorphismscomprise imm_9_116608587, imm_11_127948309, and rs1892231. In someembodiments, the at least three polymorphisms comprise imm_9_116608587,imm_11_127948309, and rs9806914. In some embodiments, the at least threepolymorphisms comprise imm_9_116608587, imm_11_127948309, andimm_21_44478192. In some embodiments, the at least three polymorphismscomprise imm_9_116608587, imm_11_127948309, and imm_21_44479552. In someembodiments, the at least three polymorphisms comprise imm_9_116608587,rs1892231, and rs9806914. In some embodiments, the at least threepolymorphisms comprise imm_9_116608587, rs1892231, and imm_21_44478192.In some embodiments, the at least three polymorphisms compriseimm_9_116608587, rs1892231, and imm_21_44479552. In some embodiments,the at least three polymorphisms comprise imm_9_116608587, rs9806914,and imm_21_44478192. In some embodiments, the at least threepolymorphisms comprise imm_9_116608587, rs9806914, and imm_21_44479552.In some embodiments, the at least three polymorphisms compriseimm_9_116608587, imm_21_44478192, and imm_21_44479552. In someembodiments, the at least three polymorphisms comprise imm_11_127948309,rs1892231, and rs9806914. In some embodiments, the at least threepolymorphisms comprise imm_11_127948309, rs1892231, and imm_21_44478192.In some embodiments, the at least three polymorphisms compriseimm_11_127948309, rs1892231, and imm_21_44479552. In some embodiments,the at least three polymorphisms comprise imm_11_127948309, rs9806914,and imm_21_44478192. In some embodiments, the at least threepolymorphisms comprise imm_11_127948309, rs9806914, and imm_21_44479552.In some embodiments, the at least three polymorphisms compriseimm_11_127948309, imm_21_44478192, and imm_21_44479552. In someembodiments, the at least three polymorphisms comprise rs1892231,rs9806914, and imm_21_44478192. In some embodiments, the at least threepolymorphisms comprise rs1892231, rs9806914, and imm_21_44479552. Insome embodiments, the at least three polymorphisms comprise rs1892231,imm_21_44478192, and imm_21_44479552. In some embodiments, the at leastthree polymorphisms comprise rs9806914, imm_21_44478192, andimm_21_44479552. In some embodiments, the at least three polymorphismsare detected in the sample obtained from the subject by a process of:(a) subjecting the sample obtained from the subject to an assayconfigured to detect at least 10 contiguous nucleic acid molecules in atleast three nucleic acid sequences within SEQ ID NOS: 1-41, or 57-59,the at least 10 contiguous nucleic acid molecules comprising a riskallele at a nucleoposition 251 or 501 within SEQ ID NOS: 1-41, or 57-59;and (b) detecting the at least 10 contiguous nucleic acid molecules inthe at least three nucleic acid sequences within SEQ ID NOS: 1-41, or57-59. In some embodiments, the assay is selected from the groupconsisting of polymerase chain reaction (PCR), quantitativereverse-transcription PCR (qPCR), automated sequencing, genotype array,or a combination thereof. In some embodiments, the inflammatory diseaseor condition is selected from the group consisting of inflammatory boweldisease (IBD), Crohn's disease (CD), obstructive CD, ulcerative colitis(UC), intestinal fibrosis, intestinal fibrostenosis, and primarysclerosing cholangitis. In some embodiments, the CD is ileal,ileocolonic, or colonic CD. In some embodiments, the subject has, or isat risk for developing, a non-response or loss-of-response to a standardtherapy, the standard therapy selected from the group consisting ofglucocorticosteriods, anti-TNF therapy, anti-a4-b7 therapy(vedolizumab), anti-IL12p40 therapy (ustekinumab), Thalidomide, andCytoxan. In some embodiments, the inhibitor of TL1A is an anti-TL1Aantibody or antigen-binding fragment. In some embodiments, the anti-TL1Aantibody binds to the same region of human TL1A as a reference antibody,the reference antibody is selected from Table 2B. In some embodiments,the anti-TL1A antibody is a neutralizing TL1A antibody orantigen-binding fragment.

Aspects disclosed herein provide methods of selecting a subject fortreatment with an inhibitor of TL1A activity or expression, the methodcomprising: (a) contacting a sample obtained from a subject comprisinggenetic material with an assay adapted to detect a presence of agenotype, the genotype comprising at least three polymorphisms providedin Table 1; and (b) selecting the subject for treatment with aninhibitor of TL1A activity or expression, provided the presence of thegenotype is detected in (a). In some embodiments, methods furthercomprise administering or prescribing to the subject a therapeuticallyeffective amount of the inhibitor of TL1A activity or expression. Insome embodiments, methods further comprise determining whether thesubject is at risk of developing a non-response or loss-of-response to astandard therapy, the standard therapy selected from the groupconsisting of glucocorticosteriods, anti-TNF therapy, anti-a4-b7 therapy(vedolizumab), anti-IL12p40 therapy (ustekinumab), Thalidomide, andCytoxin. In some embodiments, the inhibitor of TL1A is an anti-TL1Aantibody or antigen-binding fragment. In some embodiments, the anti-TL1Aantibody binds to the same region of human TL1A as a reference antibody,the reference antibody is selected from Table 2B. In some embodiments,the anti-TL1A antibody is a neutralizing TL1A antibody orantigen-binding fragment. In some embodiments, the at least threepolymorphisms is selected from the group consisting of rs11897732,rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557,rs4246905, rs10974900, rs12434976, rs16901748, rs2815844, rs889702,rs2409750, rs1541020, rs4942248, rs12934476, rs12457255, rs2297437,rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663,rs1892231, rs951279, rs9806914, rs7935393, rs1690492, rs420726,rs7759385, rs10974900, rs1326860, rs2548147, rs2815844, rs889702,rs9806914, rs6478109, rs7278257, and rs11221332. In some embodiments, apolymorphism of the at least three polymorphisms comprises a minorallele provided in Table 1. In some embodiments, a polymorphism of theat least three polymorphisms comprises a major allele provided inTable 1. In some embodiments, the genotype is heterozygous. In someembodiments, the genotype is homozygous. In some embodiments, the atleast three polymorphisms are selected from the group consisting of a“G” allele at rs11897732, an “A” allele at rs6740739, a “G” allele atrs17796285, an “A” allele at rs7935393, a “G” allele at rs12934476, an“A” allele at rs12457255, an “A” allele at rs2070557, an “A” allele atrs4246905, an “A” allele at rs10974900, a “C” allele at rs12434976, an“A” allele at rs16901748, an “A” allele at rs2815844, a “G” allele atrs889702, a “C” allele at rs2409750, an “A” allele at rs1541020, a “T”allele at rs4942248, a “G” allele at rs12934476, an “A” allele atrs12457255, an “A” allele at rs2297437, a “G” allele at rs41309367, an“A” allele at rs10733509, a “G” allele at rs10750376, a “G” allele atrs10932456, an “A” allele at rs1326860, a “G” allele at rs1528663, a “C”allele at rs1892231, an “A” allele at rs951279, an “A” allele atrs9806914, an “A” allele at rs7935393, a “G” allele at rs1690492, an “A”allele at rs420726, a “T” allele at rs7759385, an “A” allele atrs10974900, an “A” allele at rs1326860, a “C” allele at rs2548147, an“A” allele at rs2815844, a “G” allele at rs889702, an “A” allele atrs9806914, an “A” allele at rs6478109, a “C” allele at rs7278257, and an“A” allele at rs11221332. In some embodiments, the at least threepolymorphisms comprise imm_9_116608587, imm_11_127948309, and rs1892231.In some embodiments, the at least three polymorphisms compriseimm_9_116608587, imm_11_127948309, and rs9806914. In some embodiments,the at least three polymorphisms comprise imm_9_116608587,imm_11_127948309, and imm_21_44478192. In some embodiments, the at leastthree polymorphisms comprise imm_9_116608587, imm_11_127948309, andimm_21_44479552. In some embodiments, the at least three polymorphismscomprise imm_9_116608587, rs1892231, and rs9806914. In some embodiments,the at least three polymorphisms comprise imm_9_116608587, rs1892231,and imm_21_44478192. In some embodiments, the at least threepolymorphisms comprise imm_9_116608587, rs1892231, and imm_21_44479552.In some embodiments, the at least three polymorphisms compriseimm_9_116608587, rs9806914, and imm_21_44478192. In some embodiments,the at least three polymorphisms comprise imm_9_116608587, rs9806914,and imm_21_44479552. In some embodiments, the at least threepolymorphisms comprise imm_9_116608587, imm_21_44478192, andimm_21_44479552. In some embodiments, the at least three polymorphismscomprise imm_11_127948309, rs1892231, and rs9806914. In someembodiments, the at least three polymorphisms comprise imm_11_127948309,rs1892231, and imm_21_44478192. In some embodiments, the at least threepolymorphisms comprise imm_11_127948309, rs1892231, and imm_21_44479552.In some embodiments, the at least three polymorphisms compriseimm_11_127948309, rs9806914, and imm_21_44478192. In some embodiments,the at least three polymorphisms comprise imm_11_127948309, rs9806914,and imm_21_44479552. In some embodiments, the at least threepolymorphisms comprise imm_11_127948309, imm_21_44478192, andimm_21_44479552. In some embodiments, the at least three polymorphismscomprise rs1892231, rs9806914, and imm_21_44478192. In some embodiments,the at least three polymorphisms comprise rs1892231, rs9806914, andimm_21_44479552. In some embodiments, the at least three polymorphismscomprise rs1892231, imm_21_44478192, and imm_21_44479552. In someembodiments, the at least three polymorphisms comprise rs9806914,imm_21_44478192, and imm_21_44479552.

Aspects disclosed herein provide methods of treating at least one of aninflammatory, a fibrotic, and a fibrostenotic disease or condition in asubject, the method comprising: (a) determining whether a subject is, oris at risk for developing, non-response or loss-of-response to astandard therapy; (b) determining whether the subject is suitable fortreatment with an inhibitor of TL1A activity or expression by a processof: (i) contacting a sample obtained from the subject with an assayadapted to detect a presence of a genotype, the genotype comprising atleast three polymorphisms selected from Table 1; and (ii) detecting thegenotype in the sample obtained from the subject; and (c) if the subjectis not determined to have, or be at risk for developing, thenon-response or loss-of-response to the standard therapy, then treatingthe subject by administering a therapeutically effective amount of thestandard therapy to the subject; and (d) if the subject is determined tohave, or be at risk for developing, the non-response or loss-of-responseto the standard therapy, and the subject is determined to be suitablefor treatment with the inhibitor of TL1A activity or expression, thentreating the subject by administering a therapeutically effective amountof the inhibitor of TL1A activity or expression to the subject. In someembodiments, the at least three polymorphisms is selected from the groupconsisting of rs11897732, rs6740739, rs17796285, rs7935393, rs12934476,rs12457255, rs2070557, rs4246905, rs10974900, rs12434976, rs16901748,rs2815844, rs889702, rs2409750, rs1541020, rs4942248, rs12934476,rs12457255, rs2297437, rs41309367, rs10733509, rs10750376, rs10932456,rs1326860, rs1528663, rs1892231, rs951279, rs9806914, rs7935393,rs1690492, rs420726, rs7759385, rs10974900, rs1326860, rs2548147,rs2815844, rs889702, rs9806914, rs6478109, rs7278257, and rs11221332. Insome embodiments, a polymorphism of the at least three polymorphismscomprises a minor allele provided in Table 1. In some embodiments, apolymorphism of the at least three polymorphisms comprises a majorallele provided in Table 1. In some embodiments, the genotype isheterozygous. In some embodiments, the genotype is homozygous. In someembodiments, the at least three polymorphisms are selected from thegroup consisting of a “G” allele at rs11897732, an “A” allele atrs6740739, a “G” allele at rs17796285, an “A” allele at rs7935393, a “G”allele at rs12934476, an “A” allele at rs12457255, an “A” allele atrs2070557, an “A” allele at rs4246905, an “A” allele at rs10974900, a“C” allele at rs12434976, an “A” allele at rs16901748, an “A” allele atrs2815844, a “G” allele at rs889702, a “C” allele at rs2409750, an “A”allele at rs1541020, a “T” allele at rs4942248, a “G” allele atrs12934476, an “A” allele at rs12457255, an “A” allele at rs2297437, a“G” allele at rs41309367, an “A” allele at rs10733509, a “G” allele atrs10750376, a “G” allele at rs10932456, an “A” allele at rs1326860, a“G” allele at rs1528663, a “C” allele at rs1892231, an “A” allele atrs951279, an “A” allele at rs9806914, an “A” allele at rs7935393, a “G”allele at rs1690492, an “A” allele at rs420726, a “T” allele atrs7759385, an “A” allele at rs10974900, an “A” allele at rs1326860, a“C” allele at rs2548147, an “A” allele at rs2815844, a “G” allele atrs889702, an “A” allele at rs9806914, an “A” allele at rs6478109, a “C”allele at rs7278257, and an “A” allele at rs11221332. In someembodiments, the at least three polymorphisms comprise imm_9_116608587,imm_11_127948309, and rs1892231. In some embodiments, the at least threepolymorphisms comprise imm_9_116608587, imm_11_127948309, and rs9806914.In some embodiments, the at least three polymorphisms compriseimm_9_116608587, imm_11_127948309, and imm_21_44478192. In someembodiments, the at least three polymorphisms comprise imm_9_116608587,imm_11_127948309, and imm_21_44479552. In some embodiments, the at leastthree polymorphisms comprise imm_9_116608587, rs1892231, and rs9806914.In some embodiments, the at least three polymorphisms compriseimm_9_116608587, rs1892231, and imm_21_44478192. In some embodiments,the at least three polymorphisms comprise imm_9_116608587, rs1892231,and imm_21_44479552. In some embodiments, the at least threepolymorphisms comprise imm_9_116608587, rs9806914, and imm_21_44478192.In some embodiments, the at least three polymorphisms compriseimm_9_116608587, rs9806914, and imm_21_44479552. In some embodiments,the at least three polymorphisms comprise imm_9_116608587,imm_21_44478192, and imm_21_44479552. In some embodiments, the at leastthree polymorphisms comprise imm_11_127948309, rs1892231, and rs9806914.In some embodiments, the at least three polymorphisms compriseimm_11_127948309, rs1892231, and imm_21_44478192. In some embodiments,the at least three polymorphisms comprise imm_11_127948309, rs1892231,and imm_21_44479552. In some embodiments, the at least threepolymorphisms comprise imm_11_127948309, rs9806914, and imm_21_44478192.In some embodiments, the at least three polymorphisms compriseimm_11_127948309, rs9806914, and imm_21_44479552. In some embodiments,the at least three polymorphisms comprise imm_11_127948309,imm_21_44478192, and imm_21_44479552. In some embodiments, the at leastthree polymorphisms comprise rs1892231, rs9806914, and imm_21_44478192.In some embodiments, the at least three polymorphisms comprisers1892231, rs9806914, and imm_21_44479552. In some embodiments, the atleast three polymorphisms comprise rs1892231, imm_21_44478192, andimm_21_44479552. In some embodiments, the at least three polymorphismscomprise rs9806914, imm_21_44478192, and imm_21_44479552. In someembodiments, the standard therapy is selected from the group consistingof glucocorticosteriods, anti-TNF therapy, anti-a4-b7 therapy(vedolizumab), anti-IL12p40 therapy (ustekinumab), Thalidomide, andCytoxin.

Additional aspects and advantages of the present disclosure will becomereadily apparent to those skilled in this art from the followingdetailed description, wherein only illustrative embodiments of thepresent disclosure are shown and described. As will be realized, thepresent disclosure is capable of other and different embodiments, andits several details are capable of modifications in various obviousrespects, all without departing from the disclosure. Accordingly, thedrawings and description are to be regarded as illustrative in nature,and not as restrictive.

INCORPORATION BY REFERENCE

All publications, patents, and patent applications mentioned in thisspecification are herein incorporated by reference to the same extent asif each individual publication, patent, or patent application wasspecifically and individually indicated to be incorporated by reference.To the extent publications and patents or patent applicationsincorporated by reference contradict the disclosure contained in thespecification, the specification is intended to supersede and/or takeprecedence over any such contradictory material.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the inventive concepts set forth withparticularity in the appended claims. A better understanding of thefeatures and advantages of the present invention will be obtained byreference to the following detailed description that sets forthillustrative embodiments, in which the principles of the invention areutilized, and the accompanying drawings (also “Figure” and “FIG.”herein), of which:

FIG. 1 shows a workflow according to an embodiment of the presentdisclosure for processing a biological sample obtained from a subject toinform the selection of a therapeutic agent to treat a disease or acondition of the subject.

FIG. 2 shows a computer-implemented workflow according to an embodimentof the present disclosure for generating an electronic report to a user,such as a physician, comprising a TNFSF15 profile of a subject based onan analysis of genotype data from the subject.

FIG. 3 shows a computer system that is programmed or otherwiseconfigured to implement methods provided herein.

FIG. 4 shows a computer-implemented workflow according to an embodimentof the present disclosure for producing a TNFSF15 profile.

FIG. 5A-5C shows a clustering analysis within our the TL1A companiondiagnostic (CDx) dataset, FIG. 5A shows cluster 1, FIG. 5B shows cluster2, and FIG. 5C shows cluster 3, from the TL1A CDx dataset.

FIG. 6 shows that the 3 clusters from FIG. 5A-5C were collapsed into 2clusters (high TL1A expression clusters shown on the left) and (low TL1Aexpression clusters on the right).

DETAILED DESCRIPTION

Provided herein are methods, systems, and kits for identifying a subjectwho may be suitable for treatment with an inhibitor of Tumor NecrosisFactor (Ligand) Superfamily, Member 15 (TL1A) activity or expression,provided the subject is a carrier of a genotype. The subject may be apatient, who may be diagnosed with an inflammatory disease, afibrostenotic disease, or a fibrotic disease, such as inflammatory boweldisease (IBD) or Crohn's disease (CD). The subject may not be a patient,but may be suspected of having the inflammatory disease, thefibrostenotic disease, or the fibrotic disease. The genotype may, insome cases, be useful for characterizing the inflammatory fibrostenotic,or fibrotic disease or condition, as mediated by TL1A. The subject, insome embodiments, is treated by administering the inhibitor of TL1Aactivity or expression (e.g., anti-TL1A antibody) to the subject,provided the genotype is detected. In some cases, identifying thesubject as being suitable for treatment with the inhibitor of activityor expression is required in order to administer the inhibitor to thesubject.

Referring to FIG. 1, the methods, systems and kits of the presentdisclosure involve, in some embodiments, the steps of providing a buccalswab sample from a subject 101, optionally purifying DNA from the sampleby processing the sample 102, assaying the optionally processed sampleto detect genotypes of at least three genetic loci in the sample 103,processing the genotypes to produce a TNFSF15 profile 104, and selectinga therapy to treat a disease or disorder of the subject based on theTNFSF15 profile 105.

The genotypes described herein are detected using suitable genotypingdevices (e.g., array, sequencing). In some instances, a sample isobtained from the subject or patient indirectly or directly. In someinstances, the sample may be obtained by the subject. In otherinstances, the sample may be obtained by a healthcare professional, suchas a nurse or physician. The sample may be derived from virtually anybiological fluid or tissue containing genetic information, such asblood.

The subject disclosed herein can be a mammal, such as for example amouse, rat, guinea pig, rabbit, non-human primate, or farm animal. Insome instances, the subject is human. In some instances, the subject issuffering from a symptom related to a disease or condition disclosedherein (e.g., abdominal pain, cramping, diarrhea, rectal bleeding,fever, weight loss, fatigue, loss of appetite, dehydration, andmalnutrition, anemia, or ulcers).

In some embodiments, the subject is susceptible to, or is inflictedwith, thiopurine toxicity, or a disease caused by thiopurine toxicity(such as pancreatitis or leukopenia). The subject may experience, or issuspected of experiencing, non-response or loss-of-response to astandard treatment (e.g., anti-TNF alpha therapy, anti-a4-b7 therapy(vedolizumab), anti-IL12p40 therapy (ustekinumab), Thalidomide, orCytoxin).

The disease or condition disclosed herein may be an inflammatorydisease, a fibrostenotic disease, or a fibrotic disease. In someinstances, the disease or the condition is a TL1A-mediated disease orcondition. The term, “TL1A-mediated disease or condition” refers to adisease or a condition pathology or pathogenesis that is driven, atleast in part, by TL1A signaling. In some instances, the disease or thecondition is immune-mediated disease or condition, such as thosemediated by TL1A.

In some embodiments the disease or the condition is an inflammatorydisease or disorder that is mediated, at least in part, by TL1Asignaling. Non-limiting examples of inflammatory disease include,allergy, ankylosing spondylitis, asthma, atopic dermatitis, autoimmunediseases or disorders, cancer, celiac disease, chronic obstructivepulmonary disease (COPD), chronic peptic ulcer, cystic fibrosis,diabetes (e.g., type 1 diabetes and type 2 diabetes),glomerulonephritis, gout, hepatitis (e.g., active hepatitis), animmune-mediated disease or disorder, inflammatory bowel disease (IBD)such as Crohn's disease and ulcerative colitis, myositis,osteoarthritis, pelvic inflammatory disease (PID), multiple sclerosis,neurodegenerative diseases of aging, periodontal disease (e.g.,periodontitis), preperfusion injury transplant rejection, psoriasis,pulmonary fibrosis, rheumatic disease, scleroderma, sinusitis,tuberculosis.

In some embodiments, the disease or the condition is an autoimmunedisease that is mediated, at least in part, by TL1A signaling.Non-limiting examples of autoimmune disease or disorder includeAchalasia, Addison's disease, Adult Still's disease, Agammaglobulinemia,Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBMnephritis, Antiphospholipid syndrome, Autoimmune angioedema, Autoimmunedysautonomia, Autoimmune encephalomyelitis, Autoimmune hepatitis,Autoimmune inner ear disease (AIED), Autoimmune myocarditis, Autoimmuneoophoritis, Autoimmune orchitis, Autoimmune pancreatitis, Autoimmuneretinopathy, Autoimmune urticaria, Axonal & neuronal neuropathy (AMAN),Baló disease, Behcet's disease, Benign mucosal pemphigoid, Bullouspemphigoid, Castleman disease (CD), Celiac disease, Chagas disease,Chronic inflammatory demyelinating polyneuropathy (CIDP), Chronicrecurrent multifocal osteomyelitis (CRMO), Churg-Strauss Syndrome (CSS)or Eosinophilic Granulomatosis (EGPA), Cicatricial pemphigoid, Cogan'ssyndrome, Cold agglutinin disease, Congenital heart block, Coxsackiemyocarditis, CREST syndrome, Crohn's disease, Dermatitis herpetiformis,Dermatomyositis, Devic's disease (neuromyelitis optica), Discoid lupus,Dressler's syndrome, Endometriosis, Eosinophilic esophagitis (EoE),Eosinophilic fasciitis, Erythema nodosum, Essential mixedcryoglobulinemia, Evans syndrome, Fibromyalgia, Fibrosing alveolitis,Giant cell arteritis (temporal arteritis), Giant cell myocarditis,Glomerulonephritis, Goodpasture's syndrome, Granulomatosis withPolyangiitis, Graves' disease, Guillain-Barre syndrome, Hashimoto'sthyroiditis, Hemolytic anemia, Henoch-Schonlein purpura (HSP), Herpesgestationis or pemphigoid gestationis (PG), Hidradenitis Suppurativa(HS) (Acne Inversa), Hypogammalglobulinemia, IgA Nephropathy,IgG4-related sclerosing disease, Immune thrombocytopenic purpura (ITP),Inclusion body myositis (IBM), Interstitial cystitis (IC), Juvenilearthritis, Juvenile diabetes (Type 1 diabetes), Juvenile myositis (JM),Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis,Lichen planus, Lichen sclerosus, Ligneous conjunctivitis, Linear IgAdisease (LAD), Lupus, Lyme disease chronic, Meniere's disease,Microscopic polyangiitis (MPA), Mixed connective tissue disease (MCTD),Mooren's ulcer, Mucha-Habermann disease, Multifocal Motor Neuropathy(MMN) or MMNCB, Multiple sclerosis, Myasthenia gravis, Myositis,Narcolepsy, Neonatal Lupus, Neuromyelitis optica, Neutropenia, Ocularcicatricial pemphigoid, Optic neuritis, Palindromic rheumatism (PR),PANDAS, Paraneoplastic cerebellar degeneration (PCD), Paroxysmalnocturnal hemoglobinuria (PNH), Parry Romberg syndrome, Pars planitis(peripheral uveitis), Parsonage-Turner syndrome, Pemphigus, Peripheralneuropathy, Perivenous encephalomyelitis, Pernicious anemia (PA), POEMSsyndrome, Polyarteritis nodosa, Polyglandular syndromes type I, II, III,Polymyalgia rheumatica, Polymyositis, Postmyocardial infarctionsyndrome, Postpericardiotomy syndrome, Primary biliary cirrhosis,Primary sclerosing cholangitis, Progesterone dermatitis, Psoriasis,Psoriatic arthritis, Pure red cell aplasia (PRCA), Pyoderma gangrenosum,Raynaud's phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy,Relapsing polychondritis, Restless legs syndrome (RLS), Retroperitonealfibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidtsyndrome, Scleritis, Scleroderma, Sjögren's syndrome, Sperm & testicularautoimmunity, Stiff person syndrome (SPS), Subacute bacterialendocarditis (SBE), Susac's syndrome, Sympathetic ophthalmia (SO),Takayasu's arteritis, Temporal arteritis/Giant cell arteritis,Thrombocytopenic purpura (TTP), Tolosa-Hunt syndrome (THS), Transversemyelitis, Type 1 diabetes, Ulcerative colitis (UC), Undifferentiatedconnective tissue disease (UCTD), Uveitis, Vasculitis, Vitiligo, andVogt-Koyanagi-Harada Disease.

In some embodiments, the disease or the condition is a cancer that ismediated, at least in part, by TL1A signaling. Non-limiting examples ofcancers include Adenoid Cystic Carcinoma, Adrenal Gland Cancer,Amyloidosis, Anal Cancer, Ataxia-Telangiectasia, Atypical Mole Syndrome,Basal Cell Carcinoma, Bile Duct Cancer, Birt Hogg Dube Syndrome, BladderCancer, Bone Cancer, Brain Tumor, Breast Cancer, Breast Cancer in Men,Carcinoid Tumor, Cervical Cancer, Colorectal Cancer, Ductal Carcinoma,Endometrial Cancer, Esophageal Cancer, Gastric Cancer, GastrointestinalStromal Tumor (GIST), HER2-Positive Breast Cancer, Islet Cell Tumor,Juvenile Polyposis Syndrome, Kidney Cancer, Laryngeal Cancer,Leukemia—Acute Lymphoblastic Leukemia, Leukemia—Acute Lymphocytic (ALL),Leukemia—Acute Myeloid AML, Leukemia—Adult, Leukemia—Childhood,Leukemia—Chronic Lymphocytic (CLL), Leukemia—Chronic Myeloid (CML),Liver Cancer, Lobular Carcinoma, Lung Cancer, Lung Cancer—Small Cell(SCLC), Lung Cancer—Non-small Cell (NSCLC), Lymphoma—Hodgkin's,Lymphoma—Non-Hodgkin's, Malignant Glioma, Melanoma, Meningioma, MultipleMyeloma, Myelodysplastic Syndrome (MDS), Nasopharyngeal Cancer,Neuroendocrine Tumor, Oral Cancer, Osteosarcoma, Ovarian Cancer,Pancreatic Cancer, Pancreatic Neuroendocrine Tumors, Parathyroid Cancer,Penile Cancer, Peritoneal Cancer, Peutz-Jeghers Syndrome, PituitaryGland Tumor, Polycythemia Vera, Prostate Cancer, Renal Cell Carcinoma,Retinoblastoma, Salivary Gland Cancer, Sarcoma, Sarcoma—Kaposi, SkinCancer, Small Intestine Cancer, Stomach Cancer, Testicular Cancer,Thymoma, Thyroid Cancer, Uterine (Endometrial) Cancer, Vaginal Cancer,and Wilms' Tumor.

In some embodiments, the disease or the condition is an inflammatorybowel disease, such as Crohn's disease (CD) or ulcerative colitis (UC).A subject may suffer from fibrosis, fibrostenosis, or a fibroticdisease, either isolated or in combination with an inflammatory disease.In some cases, the CD is severe CD. The severe CD may result frominflammation that has led to the formation of scar tissue in theintestinal wall (fibrostenosis) and/or swelling. In some cases, thesevere CD is characterized by the presence of fibrotic and/orinflammatory strictures. The strictures may be determined by computedtomography enterography (CTE), and magnetic resonance imagingenterography (MRE). The disease or condition may be characterized asrefractory, which in some cases, means the disease is resistant to astandard treatment (e.g., anti-TNFα therapy). Non-limiting examples ofstandard treatment include glucocorticosteriods, anti-TNF therapy,anti-a4-b7 therapy (vedolizumab), anti-IL12p40 therapy (ustekinumab),Thalidomide, and Cytoxin.

Genotypes

Disclosed herein are genotypes that may be detected in a sample obtainedfrom a subject by analyzing the genetic material in the sample. In someinstances, the subject may be human. In some embodiments, the geneticmaterial is obtained from a subject having a disease or conditiondisclosed herein. In some cases, the genetic material is obtained fromblood, serum, plasma, sweat, hair, tears, urine, and other techniquesknown by one of skill in the art. In some cases, the genetic material isobtained from a biopsy, e.g., from the intestinal track of the subject.

The genotypes of the present disclosure comprise genetic material thatis deoxyribonucleic acid (DNA). In some instances, the genotypecomprises a denatured DNA molecule or fragment thereof. In someinstances, the genotype comprises DNA selected from: genomic DNA, viralDNA, mitochondrial DNA, plasmid DNA, amplified DNA, circular DNA,circulating DNA, cell-free DNA, or exosomal DNA. In some instances, theDNA is single-stranded DNA (ssDNA), double-stranded DNA, denaturingdouble-stranded DNA, synthetic DNA, and combinations thereof. Thecircular DNA may be cleaved or fragmented.

The genotypes disclosed herein comprise at least one polymorphism at agene or genetic locus described herein. In some instances, the gene orgenetic locus is selected from the group consisting of Tumor NecrosisFactor (Ligand) Superfamily, Member 15 (TNFSF15), THADA Armadillo RepeatContaining (THADA), Pleckstrin Homology, MyTH4 And FERM DomainContaining H2 (PLEKHH2), XK Related 6 (XKR6), Myotubularin RelatedProtein 9 (MTMR9), ETS Proto-Oncogene 1, Transcription Factor (ETS1),C-Type Lectin Domain Containing 16A (CLEC16A), Suppressor Of CytokineSignaling 1 (SOCS1), Protein Tyrosine Phosphatase Non-Receptor Type 2(PTPN2), Inducible T Cell Costimulator Ligand (ICOSLG), Janus Kinase 2(JAK2), Catenin Delta 2 (CTNND2), Regulator Of G Protein Signaling 7(RGS7), RNA Binding Fox-1 Homolog 1 (RBFOX1), RNA Binding Motif Protein17 (RBM17), 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3(PFKFB3), Ecto-NOX Disulfide-Thiol Exchanger 1 (ENOXI), Coiled-CoilDomain Containing 122 (CCDC122), Regulator Of Telomere ElongationHelicase 1 (RTEL1), TNF Receptor Superfamily Member 6b (TNFRSF6B), GLISFamily Zinc Finger 3 (GLIS3), Solute Carrier Family 1 Member 1 (SLC1A1),IKAROS Family Zinc Finger 2 (IKZF2), Fatty Acyl-CoA Reductase 1 (FAR1),Spondin 1(SPON1), Plexin A2 (PLXNA2), MIR205 Host Gene (MIR205HG),C-Type Lectin Domain Containing 16A (CLEC16A), PR/SET Domain 14 (PRDM),Autophagy Related 5 (ATG5), and Prostaglandin E Receptor 4 (PTGER4). Insome instances, the gene or genetic locus comprises a gene or geneticlocus provided in Table 1. The genotypes disclosed herein are, in somecases, a haplotype. In some instances, the genotype comprises aparticular polymorphism, a polymorphism in linkage disequilibrium (LD)therewith, or a combination thereof. In some cases, LD is defined by anr² of at least or about 0.70, 0.75, 0.80, 0.85, 0.90, or 1.0. Thegenotypes disclosed herein can comprise at least or about 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, or more polymorphisms. In preferred embodiments,the genotypes disclosed herein comprise a combination of 3polymorphisms, such as those provided in Table 1.

The polymorphisms described herein can be a single nucleotidepolymorphism, or an indel (insertion/deletion). In some instances, thepolymorphism is an insertion or a deletion of at least one nucleobase(e.g., an indel). In some instances, the genotype may comprise a copynumber variation (CNV), which is a variation in a number of a nucleicacid sequence between individuals in a given population. In someinstances, the CNV comprises at least or about two, three, four, five,six, seven, eight, nine, ten, twenty, thirty, forty or fifty nucleicacid molecules. In some instances, the genotype is heterozygous. In someinstances, the genotype is homozygous.

Disclosed herein, in the following embodiments, are genotypes disclosedherein:

-   1. A genotype comprising at least one polymorphism at a gene or    genetic locus.-   2. The genotype of embodiment 1 comprising a polymorphism provided    in Table 1.-   3. The genotype of embodiments 1-2 that is heterozygous.-   4. The genotype of embodiments 1-2 that is homozygous.-   5. The genotype of embodiments 1-4, wherein the genotype comprises    at least two polymorphisms.-   6. The genotype of embodiments 1-4, wherein the genotype comprises    at least three polymorphisms.-   7. The genotype of embodiments 1-4, wherein the genotype comprises    at least four polymorphisms.-   8. The genotype of embodiment 1, comprising a polymorphism in    linkage disequilibrium with a polymorphism provided in Table 1.-   9. The genotype of embodiment 8, wherein LD is defined by (i) a D′    value of at least about 0.70, or (ii) a D′ value of 0 and an r²    value of at least about 0.70.-   10. The genotype of embodiment 8, wherein LD is defined by (i) a D′    value of at least about 0.80, or (ii) a D′ value of 0 and an r²    value of at least about 0.80.-   11. The genotype of embodiment 8, wherein LD is defined by (i) a D′    value of at least about 0.90, or (ii) a D′ value of 0 and an r²    value of at least about 0.90.-   12. The genotype of embodiment 8, wherein LD is defined by (i) a D′    value of at least about 0.95, or (ii) a D′ value of 0 and an r²    value of at least about 0.95.-   13. The genotype of embodiments 1-12, wherein the gene or genetic    locus is selected from the group consisting of Tumor Necrosis Factor    (Ligand) Superfamily, Member 15 (TNFSF15), THADA Armadillo Repeat    Containing (THADA), Pleckstrin Homology, MyTH4 And FERM Domain    Containing H2 (PLEKHH2), XK Related 6 (XKR6), Myotubularin Related    Protein 9 (MTMR9), ETS Proto-Oncogene 1, Transcription Factor    (ETS1), C-Type Lectin Domain Containing 16A (CLEC16A), Suppressor Of    Cytokine Signaling 1 (SOCS1), Protein Tyrosine Phosphatase    Non-Receptor Type 2 (PTPN2), Inducible T Cell Costimulator Ligand    (ICOSLG), Janus Kinase 2 (JAK2), Catenin Delta 2 (CTNND2), Regulator    Of G Protein Signaling 7 (RGS7), RNA Binding Fox-1 Homolog 1    (RBFOX1), RNA Binding Motif Protein 17 (RBM17),    6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3 (PFKFB3),    Ecto-NOX Disulfide-Thiol Exchanger 1 (ENOXI), Coiled-Coil Domain    Containing 122 (CCDC122), Regulator Of Telomere Elongation Helicase    1 (RTEL1), TNF Receptor Superfamily Member 6b (TNFRSF6B), GLIS    Family Zinc Finger 3 (GLIS3), Solute Carrier Family 1 Member 1    (SLC1A1), IKAROS Family Zinc Finger 2 (IKZF2), Fatty Acyl-CoA    Reductase 1 (FAR1), Spondin 1(SPON1), Plexin A2 (PLXNA2), MIR205    Host Gene (MIR205HG), C-Type Lectin Domain Containing 16A (CLEC16A),    PR/SET Domain 14 (PRDM), Autophagy Related 5 (ATG5), and    Prostaglandin E Receptor 4 (PTGER4).-   14. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from:    -   (1) rs16901748, rs7759385, rs4246905;    -   (2) rs16901748, rs7759385, rs7935393;    -   (3) rs16901748, rs7759385, rs1892231;    -   (4) rs16901748, rs7759385, rs12934476;    -   (5) rs16901748, rs7759385, rs9806914;    -   (6) rs16901748, rs7759385, rs2297437;    -   (7) rs16901748, rs7759385, rs2070557;    -   (8) rs16901748, rs7759385, rs7278257;    -   (9) rs16901748, rs7759385, rs11221332;    -   (10) rs16901748, rs7759385, rs41309367;    -   (11) rs16901748, rs7759385, rs6478109;    -   (12) rs16901748, rs4246905, rs7935393;    -   (13) rs16901748, rs4246905, rs1892231;    -   (14) rs16901748, rs4246905, rs12934476;    -   (15) rs16901748, rs4246905, rs9806914;    -   (16) rs16901748, rs4246905, rs2297437;    -   (17) rs16901748, rs4246905, rs2070557;    -   (18) rs16901748, rs4246905, rs7278257;    -   (19) rs16901748, rs4246905, rs11221332;    -   (20) rs16901748, rs4246905, rs41309367;    -   (21) rs16901748, rs4246905, rs6478109;    -   (22) rs16901748, rs7935393, rs1892231;    -   (23) rs16901748, rs7935393, rs12934476;    -   (24) rs16901748, rs7935393, rs9806914;    -   (25) rs16901748, rs7935393, rs2297437;    -   (26) rs16901748, rs7935393, rs2070557;    -   (27) rs16901748, rs7935393, rs7278257;    -   (28) rs16901748, rs7935393, rs11221332;    -   (29) rs16901748, rs7935393, rs41309367;    -   (30) rs16901748, rs7935393, rs6478109;    -   (31) rs16901748, rs1892231, rs12934476;    -   (32) rs16901748, rs1892231, rs9806914;    -   (33) rs16901748, rs1892231, rs2297437;    -   (34) rs16901748, rs1892231, rs2070557;    -   (35) rs16901748, rs1892231, rs7278257;    -   (36) rs16901748, rs1892231, rs11221332;    -   (37) rs16901748, rs1892231, rs41309367;    -   (38) rs16901748, rs1892231, rs6478109;    -   (39) rs16901748, rs12934476, rs9806914;    -   (40) rs16901748, rs12934476, rs2297437;    -   (41) rs16901748, rs12934476, rs2070557;    -   (42) rs16901748, rs12934476, rs7278257;    -   (43) rs16901748, rs12934476, rs11221332;    -   (44) rs16901748, rs12934476, rs41309367;    -   (45) rs16901748, rs12934476, rs6478109;    -   (46) rs16901748, rs9806914, rs2297437;    -   (47) rs16901748, rs9806914, rs2070557;    -   (48) rs16901748, rs9806914, rs7278257;    -   (49) rs16901748, rs9806914, rs11221332;    -   (50) rs16901748, rs9806914, rs41309367;    -   (51) rs16901748, rs9806914, rs6478109;    -   (52) rs16901748, rs2297437, rs2070557;    -   (53) rs16901748, rs2297437, rs7278257;    -   (54) rs16901748, rs2297437, rs11221332;    -   (55) rs16901748, rs2297437, rs41309367;    -   (56) rs16901748, rs2297437, rs6478109;    -   (57) rs16901748, rs2070557, rs7278257;    -   (58) rs16901748, rs2070557, rs11221332;    -   (59) rs16901748, rs2070557, rs41309367;    -   (60) rs16901748, rs2070557, rs6478109;    -   (61) rs16901748, rs7278257, rs11221332;    -   (62) rs16901748, rs7278257, rs41309367;    -   (63) rs16901748, rs7278257, rs6478109;    -   (64) rs16901748, rs11221332, rs41309367;    -   (65) rs16901748, rs11221332, rs6478109;    -   (66) rs16901748, rs41309367, rs6478109;    -   (67) rs7759385, rs4246905, rs7935393;    -   (68) rs7759385, rs4246905, rs1892231;    -   (69) rs7759385, rs4246905, rs12934476;    -   (70) rs7759385, rs4246905, rs9806914;    -   (71) rs7759385, rs4246905, rs2297437;    -   (72) rs7759385, rs4246905, rs2070557;    -   (73) rs7759385, rs4246905, rs7278257;    -   (74) rs7759385, rs4246905, rs11221332;    -   (75) rs7759385, rs4246905, rs41309367;    -   (76) rs7759385, rs4246905, rs6478109;    -   (77) rs7759385, rs7935393, rs1892231;    -   (78) rs7759385, rs7935393, rs12934476;    -   (79) rs7759385, rs7935393, rs9806914;    -   (80) rs7759385, rs7935393, rs2297437;    -   (81) rs7759385, rs7935393, rs2070557;    -   (82) rs7759385, rs7935393, rs7278257;    -   (83) rs7759385, rs7935393, rs11221332;    -   (84) rs7759385, rs7935393, rs41309367;    -   (85) rs7759385, rs7935393, rs6478109;    -   (86) rs7759385, rs1892231, rs12934476;    -   (87) rs7759385, rs1892231, rs9806914;    -   (88) rs7759385, rs1892231, rs2297437;    -   (89) rs7759385, rs1892231, rs2070557;    -   (90) rs7759385, rs1892231, rs7278257;    -   (91) rs7759385, rs1892231, rs11221332;    -   (92) rs7759385, rs1892231, rs41309367;    -   (93) rs7759385, rs1892231, rs6478109;    -   (94) rs7759385, rs12934476, rs9806914;    -   (95) rs7759385, rs12934476, rs2297437;    -   (96) rs7759385, rs12934476, rs2070557;    -   (97) rs7759385, rs12934476, rs7278257;    -   (98) rs7759385, rs12934476, rs11221332;    -   (99) rs7759385, rs12934476, rs41309367;    -   (100) rs7759385, rs12934476, rs6478109;    -   (101) rs7759385, rs9806914, rs2297437;    -   (102) rs7759385, rs9806914, rs2070557;    -   (103) rs7759385, rs9806914, rs7278257;    -   (104) rs7759385, rs9806914, rs11221332;    -   (105) rs7759385, rs9806914, rs41309367;    -   (106) rs7759385, rs9806914, rs6478109;    -   (107) rs7759385, rs2297437, rs2070557;    -   (108) rs7759385, rs2297437, rs7278257;    -   (109) rs7759385, rs2297437, rs11221332;    -   (110) rs7759385, rs2297437, rs41309367;    -   (111) rs7759385, rs2297437, rs6478109;    -   (112) rs7759385, rs2070557, rs7278257;    -   (113) rs7759385, rs2070557, rs11221332;    -   (114) rs7759385, rs2070557, rs41309367;    -   (115) rs7759385, rs2070557, rs6478109;    -   (116) rs7759385, rs7278257, rs11221332;    -   (117) rs7759385, rs7278257, rs41309367;    -   (118) rs7759385, rs7278257, rs6478109;    -   (119) rs7759385, rs11221332, rs41309367;    -   (120) rs7759385, rs11221332, rs6478109;    -   (121) rs7759385, rs41309367, rs6478109;    -   (122) rs4246905, rs7935393, rs1892231;    -   (123) rs4246905, rs7935393, rs12934476;    -   (124) rs4246905, rs7935393, rs9806914;    -   (125) rs4246905, rs7935393, rs2297437;    -   (126) rs4246905, rs7935393, rs2070557;    -   (127) rs4246905, rs7935393, rs7278257;    -   (128) rs4246905, rs7935393, rs11221332;    -   (129) rs4246905, rs7935393, rs41309367;    -   (130) rs4246905, rs7935393, rs6478109;    -   (131) rs4246905, rs1892231, rs12934476;    -   (132) rs4246905, rs1892231, rs9806914;    -   (133) rs4246905, rs1892231, rs2297437;    -   (134) rs4246905, rs1892231, rs2070557;    -   (135) rs4246905, rs1892231, rs7278257;    -   (136) rs4246905, rs1892231, rs11221332;    -   (137) rs4246905, rs1892231, rs41309367;    -   (138) rs4246905, rs1892231, rs6478109;    -   (139) rs4246905, rs12934476, rs9806914;    -   (140) rs4246905, rs12934476, rs2297437;    -   (141) rs4246905, rs12934476, rs2070557;    -   (142) rs4246905, rs12934476, rs7278257;    -   (143) rs4246905, rs12934476, rs11221332;    -   (144) rs4246905, rs12934476, rs41309367;    -   (145) rs4246905, rs12934476, rs6478109;    -   (146) rs4246905, rs9806914, rs2297437;    -   (147) rs4246905, rs9806914, rs2070557;    -   (148) rs4246905, rs9806914, rs7278257;    -   (149) rs4246905, rs9806914, rs11221332;    -   (150) rs4246905, rs9806914, rs41309367;    -   (151) rs4246905, rs9806914, rs6478109;    -   (152) rs4246905, rs2297437, rs2070557;    -   (153) rs4246905, rs2297437, rs7278257;    -   (154) rs4246905, rs2297437, rs11221332;    -   (155) rs4246905, rs2297437, rs41309367;    -   (156) rs4246905, rs2297437, rs6478109;    -   (157) rs4246905, rs2070557, rs7278257;    -   (158) rs4246905, rs2070557, rs11221332;    -   (159) rs4246905, rs2070557, rs41309367;    -   (160) rs4246905, rs2070557, rs6478109;    -   (161) rs4246905, rs7278257, rs11221332;    -   (162) rs4246905, rs7278257, rs41309367;    -   (163) rs4246905, rs7278257, rs6478109;    -   (164) rs4246905, rs11221332, rs41309367;    -   (165) rs4246905, rs11221332, rs6478109;    -   (166) rs4246905, rs41309367, rs6478109;    -   (167) rs7935393, rs1892231, rs12934476;    -   (168) rs7935393, rs1892231, rs9806914;    -   (169) rs7935393, rs1892231, rs2297437;    -   (170) rs7935393, rs1892231, rs2070557;    -   (171) rs7935393, rs1892231, rs7278257;    -   (172) rs7935393, rs1892231, rs11221332;    -   (173) rs7935393, rs1892231, rs41309367;    -   (174) rs7935393, rs1892231, rs6478109;    -   (175) rs7935393, rs12934476, rs9806914;    -   (176) rs7935393, rs12934476, rs2297437;    -   (177) rs7935393, rs12934476, rs2070557;    -   (178) rs7935393, rs12934476, rs7278257;    -   (179) rs7935393, rs12934476, rs11221332;    -   (180) rs7935393, rs12934476, rs41309367;    -   (181) rs7935393, rs12934476, rs6478109;    -   (182) rs7935393, rs9806914, rs2297437;    -   (183) rs7935393, rs9806914, rs2070557;    -   (184) rs7935393, rs9806914, rs7278257;    -   (185) rs7935393, rs9806914, rs11221332;    -   (186) rs7935393, rs9806914, rs41309367;    -   (187) rs7935393, rs9806914, rs6478109;    -   (188) rs7935393, rs2297437, rs2070557;    -   (189) rs7935393, rs2297437, rs7278257;    -   (190) rs7935393, rs2297437, rs11221332;    -   (191) rs7935393, rs2297437, rs41309367;    -   (192) rs7935393, rs2297437, rs6478109;    -   (193) rs7935393, rs2070557, rs7278257;    -   (194) rs7935393, rs2070557, rs11221332;    -   (195) rs7935393, rs2070557, rs41309367;    -   (196) rs7935393, rs2070557, rs6478109;    -   (197) rs7935393, rs7278257, rs11221332;    -   (198) rs7935393, rs7278257, rs41309367;    -   (199) rs7935393, rs7278257, rs6478109;    -   (200) rs7935393, rs11221332, rs41309367;    -   (201) rs7935393, rs11221332, rs6478109;    -   (202) rs7935393, rs41309367, rs6478109;    -   (203) rs1892231, rs12934476, rs9806914;    -   (204) rs1892231, rs12934476, rs2297437;    -   (205) rs1892231, rs12934476, rs2070557;    -   (206) rs1892231, rs12934476, rs7278257;    -   (207) rs1892231, rs12934476, rs11221332;    -   (208) rs1892231, rs12934476, rs41309367;    -   (209) rs1892231, rs12934476, rs6478109;    -   (210) rs1892231, rs9806914, rs2297437;    -   (211) rs1892231, rs9806914, rs2070557;    -   (212) rs1892231, rs9806914, rs7278257;    -   (213) rs1892231, rs9806914, rs11221332;    -   (214) rs1892231, rs9806914, rs41309367;    -   (215) rs1892231, rs9806914, rs6478109;    -   (216) rs1892231, rs2297437, rs2070557;    -   (217) rs1892231, rs2297437, rs7278257;    -   (218) rs1892231, rs2297437, rs11221332;    -   (219) rs1892231, rs2297437, rs41309367;    -   (220) rs1892231, rs2297437, rs6478109;    -   (221) rs1892231, rs2070557, rs7278257;    -   (222) rs1892231, rs2070557, rs11221332;    -   (223) rs1892231, rs2070557, rs41309367;    -   (224) rs1892231, rs2070557, rs6478109;    -   (225) rs1892231, rs7278257, rs11221332;    -   (226) rs1892231, rs7278257, rs41309367;    -   (227) rs1892231, rs7278257, rs6478109;    -   (228) rs1892231, rs11221332, rs41309367;    -   (229) rs1892231, rs11221332, rs6478109;    -   (230) rs1892231, rs41309367, rs6478109;    -   (231) rs12934476, rs9806914, rs2297437;    -   (232) rs12934476, rs9806914, rs2070557;    -   (233) rs12934476, rs9806914, rs7278257;    -   (234) rs12934476, rs9806914, rs11221332;    -   (235) rs12934476, rs9806914, rs41309367;    -   (236) rs12934476, rs9806914, rs6478109;    -   (237) rs12934476, rs2297437, rs2070557;    -   (238) rs12934476, rs2297437, rs7278257;    -   (239) rs12934476, rs2297437, rs11221332;    -   (240) rs12934476, rs2297437, rs41309367;    -   (241) rs12934476, rs2297437, rs6478109;    -   (242) rs12934476, rs2070557, rs7278257;    -   (243) rs12934476, rs2070557, rs11221332;    -   (244) rs12934476, rs2070557, rs41309367;    -   (245) rs12934476, rs2070557, rs6478109;    -   (246) rs12934476, rs7278257, rs11221332;    -   (247) rs12934476, rs7278257, rs41309367;    -   (248) rs12934476, rs7278257, rs6478109;    -   (249) rs12934476, rs11221332, rs41309367;    -   (250) rs12934476, rs11221332, rs6478109;    -   (251) rs12934476, rs41309367, rs6478109;    -   (252) rs9806914, rs2297437, rs2070557;    -   (253) rs9806914, rs2297437, rs7278257;    -   (254) rs9806914, rs2297437, rs11221332;    -   (255) rs9806914, rs2297437, rs41309367;    -   (256) rs9806914, rs2297437, rs6478109;    -   (257) rs9806914, rs2070557, rs7278257;    -   (258) rs9806914, rs2070557, rs11221332;    -   (259) rs9806914, rs2070557, rs41309367;    -   (260) rs9806914, rs2070557, rs6478109;    -   (261) rs9806914, rs7278257, rs11221332;    -   (262) rs9806914, rs7278257, rs41309367;    -   (263) rs9806914, rs7278257, rs6478109;    -   (264) rs9806914, rs11221332, rs41309367;    -   (265) rs9806914, rs11221332, rs6478109;    -   (266) rs9806914, rs41309367, rs6478109;    -   (267) rs2297437, rs2070557, rs7278257;    -   (268) rs2297437, rs2070557, rs11221332;    -   (269) rs2297437, rs2070557, rs41309367;    -   (270) rs2297437, rs2070557, rs6478109;    -   (271) rs2297437, rs7278257, rs11221332;    -   (272) rs2297437, rs7278257, rs41309367;    -   (273) rs2297437, rs7278257, rs6478109;    -   (274) rs2297437, rs11221332, rs41309367;    -   (275) rs2297437, rs11221332, rs6478109;    -   (276) rs2297437, rs41309367, rs6478109;    -   (277) rs2070557, rs7278257, rs11221332;    -   (278) rs2070557, rs7278257, rs41309367;    -   (279) rs2070557, rs7278257, rs6478109;    -   (280) rs2070557, rs11221332, rs41309367;    -   (281) rs2070557, rs11221332, rs6478109;    -   (282) rs2070557, rs41309367, rs6478109;    -   (283) rs7278257, rs11221332, rs41309367;    -   (284) rs7278257, rs11221332, rs6478109;    -   (285) rs7278257, rs41309367, rs6478109; or    -   (286) rs11221332, rs41309367, rs6478109.-   15. The genotype of embodiment 14, wherein the rs7278257 is replaced    with rs56124762.-   16. The genotype of embodiment 14, wherein the rs7278257 is replaced    with rs2070558.-   17. The genotype of embodiment 14, wherein the rs7278257 is replaced    with rs2070561.-   18. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from imm_9_116608587,    imm_11_127948309, and rs1892231.-   19. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from imm_9_116608587,    imm_11_127948309, and rs9806914.-   20. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from imm_9_116608587,    imm_11_127948309, and imm_21_44478192.-   21. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from imm_9_116608587,    imm_11_127948309, and imm_21_44479552.-   22. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from imm_9_116608587, rs1892231,    and rs9806914.-   23. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from imm_9_116608587, rs1892231,    and imm_21_44478192.-   24. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from imm_9_116608587, rs1892231,    and imm_21_44479552.-   25. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from imm_9_116608587, rs9806914,    and imm_21_44478192.-   26. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from imm_9_116608587, rs9806914,    and imm_21_44479552.-   27. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from imm_9_116608587,    imm_21_44478192, and imm_21_44479552.-   28. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from imm_11_127948309,    rs1892231, and rs9806914.-   29. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from imm_11_127948309,    rs1892231, and imm_21_44478192.-   30. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from imm_11_127948309,    rs1892231, and imm_21_44479552.-   31. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from imm_11_127948309,    rs9806914, and imm_21_44478192.-   32. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from imm_11_127948309,    rs9806914, and imm_21_44479552.-   33. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from imm_11_127948309,    imm_21_44478192, and imm_21_44479552.-   34. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from rs1892231, rs9806914, and    imm_21_44478192.-   35. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from rs1892231, rs9806914, and    imm_21_44479552.-   36. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from rs1892231, imm_21_44478192,    and imm_21_44479552.-   37. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from rs9806914, imm_21_44478192,    and imm_21_44479552.-   38. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from rs6478109, rs56124762, and    rs1892231.-   39. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from rs6478109, rs56124762, and    rs16901748.-   40. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from rs6478109, rs1892231, and    rs16901748.-   41. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from rs56124762, rs1892231, and    rs16901748.-   42. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from rs6478109, rs2070558, and    rs1892231.-   43. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from rs6478109, rs2070558, and    rs16901748.-   44. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from rs6478109, rs1892231, and    rs16901748.-   45. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from rs2070558, rs1892231, and    rs16901748.-   46. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from rs6478109, rs2070561, and    rs1892231.-   47. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from rs6478109, rs2070561, and    rs16901748.-   48. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from rs6478109, rs1892231, and    rs16901748.-   49. The genotype of embodiments 5-6, wherein the genotype comprises    at least two polymorphisms selected from rs2070561, rs1892231, and    rs16901748.-   50. The genotype of embodiments 1-49, wherein the genotype comprises    a minor allele provided in Table 1 for at least one polymorphism.-   51. The genotype of embodiments 1-49, wherein the genotype comprises    a major allele provided in Table 1 for at least one polymorphism.-   52. The genotype of embodiments 1-51, wherein a presence of the    genotype is predictive of a positive therapeutic response to a    treatment with an inhibitor of TL1A activity of expression at a    positive predictive value of at least about 55%, 60%, 65%, 70%, 75%,    80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.-   53. The genotype of embodiments 1-55, wherein a presence of the    genotype is predictive of a positive therapeutic response to a    treatment with an inhibitor of TL1A activity of expression with a    specificity of at least about 55%, 60%, 65%, 70%, 75%, 80%, 85%,    90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%.

Aspects disclosed herein provide genotypes that are associated with, andtherefore indicative of, a subject having or being susceptible todeveloping a particular disease or condition, or a subclinical phenotypethereof. In addition, the genotypes disclosed herein are associated withan increase TNFSF15 (TL1A) expression or activity. Thus, the genotypesare indicative that the subject will have a positive therapeuticresponse to an inhibitor of TL1A activity or expression. Table 1provides exemplary polymorphisms associated with, and thereforepredictive of, a positive therapeutic response to an inhibitor ofTNFSF15 (TL1A) expression or activity. The term, “positive therapeuticresponse” refers to a reduction or an elimination of at least onesymptom of the disease or the condition (e.g., Cohn's disease) afterinduction of a therapy (e.g., anti-TL1A antibody).

TABLE 1 Exemplary Polymorphisms SEQ Minor Major ID rsID Chip_id GeneAllele Allele NO rs11897732 1 kg 2 43394890 THADA G A 1 rs6740739 1 kg 243709147 THADA, PLEKHH2 A G 2 rs17796285 1 kg 8 11161865 XKR6, MTMR9 G C3 rs7935393 imm 11 127948309 ETS1 C A 4 rs12934476 imm_16_11239010CLEC16A, SOCS1 G A 5 rs12457255 imm_18_12749976 LOC100996324, PTPN2 A C6 rs2070557 imm 21 44479552 ICOSLG A T 7 rs4246905 imm 9 116593070TNFSF15 A G 8 rs10974900 imm_9_4977958 JAK2 A G 9 rs12434976 rs12434976LINC01550,C14orf177 C A 10 rs16901748 rs16901748 CTNND2 A C 11 rs2815844rs2815844 RGS7 A G 12 rs889702 rs889702 RBFOX1 G A 13 rs2409750 1kg_8_11125104 XKR6, MTMR9 C A 14 rs1541020 imm_10_6205036 RBM17, PFKFB3A G 15 rs4942248 imm_13_43304805 ENOX1, CCDC122 T A 16 rs12934476 imm 1611239010 CLEC16A, SOCS1 G A 17 rs12457255 imm_18_12749976 LOC100996324,PTPN2 A C 18 rs2297437 imm_20 _1775718 RTEL1-TNFRSF6B A G 19 rs41309367imm_20_61779998 RTEL1-TNFRSF6B G A 20 rs10733509 imm 9 4298050 GLIS3,SLC1A1 A G 21 rs10750376 rs10750376 LOC101929497, ETS1 G A 22 rs10932456rs10932456 MIR4776-2, IKZF2 G A 23 rs1326860 rs1326860 LINC01031, NONE AG 24 rs1528663 rs1528663 FAR1, SPON1 G A 25 rs1892231 rs1892231LINC01550, C14orf177 C A 26 rs951279 rs951279 PLXNA2, MIR205HG G A 27rs9806914 rs9806914 RBFOX1 A G 28 rs7935393 imm_11_127948309 ETS1 C A 29rs1690492 imm_16_11226317 CLEC16A, SOCS1 G C 30 rs420726 imm 21 44483873ICOSLG G A 31 rs7759385 imm_6_106695463 PRDM1, ATG5 T A 32 rs10974900imm 9 4977958 JAK2 A G 33 rs1326860 rs1326860 LINC01031, NONE A G 34rs2548147 rs2548147 LINC00603, PTGER4 C G 35 rs2815844 rs2815844 RGS7 AG 36 rs889702 rs889702 RBFOX1 G A 37 rs9806914 rs9806914 RBFOX1 A G 38rs6478109 imm 9 116608587 TNFSF15 A G 39 rs7278257 imm 21 44478192ICOSLG C G 40 rs11221332 imm 11 127886184 ETS1 A G 41 rs56124762imm_21_44482902 ICOSLG A G 57 rs2070558 imm_21_44480086 ICOSLG G A 58rs2070561 rs2070561 ICOSLG T C 59

The instant disclosure provides models comprising 3 polymorphisms (e.g.,“3-SNP Models”) that, when detected in a sample obtained from a subject,indicate a positive therapeutic response in the subject to a treatment,such as with an inhibitor of TL1A activity or expression. Non-limitingexamples of models described herein include Model A (rs6478109,rs7278257, and rs1892231); Model B (rs6478109, rs2070557, andrs9806914); Model C (rs6478109, rs7935393, and rs1892231); Model D(rs6478109, rs7935393, and rs9806914); Model E (rs6478109, rs9806914,and rs16901748); Model F (rs6478109, rs16901748, and rs2297437); Model G(rs6478109, rs1892231, and rs16901748); Model H (rs6478109, rs2070557,and rs7935393); Model I (rs6478109, rs7278257, and rs7935393); Model J(rs6478109, rs9806914, and rs1892231); and Model K (rs6478109,rs7278257, and rs16901748).

Methods Methods of Detection

Methods disclosed herein for detecting a genotype in a sample from asubject comprise analyzing the genetic material in the sample to detectat least one of a presence, an absence, and a quantity of a nucleic acidsequence encompassing the genotype of interest. In some embodiments, thesample is assayed to measure a presence, absence or quantity of at leastthree polymorphisms. In some embodiments, the sample is assayed tomeasure a presence, absence, or quantity of at least four polymorphisms.In some embodiments, the sample is assayed to measure a presence,absence, or quantity of at least five polymorphisms. In someembodiments, at least three genotypes are detected, using the methodsdescribed herein.

In some cases, the nucleic acid sequence comprises DNA. In someinstances, the nucleic acid sequence comprises a denatured DNA moleculeor fragment thereof. In some instances, the nucleic acid sequencecomprises DNA selected from: genomic DNA, viral DNA, mitochondrial DNA,plasmid DNA, amplified DNA, circular DNA, circulating DNA, cell-freeDNA, or exosomal DNA. In some instances, the DNA is single-stranded DNA(ssDNA), double-stranded DNA, denaturing double-stranded DNA, syntheticDNA, and combinations thereof. The circular DNA may be cleaved orfragmented. In some instances, the nucleic acid sequence comprises RNA.In some instances, the nucleic acid sequence comprises fragmented RNA.In some instances, the nucleic acid sequence comprises partiallydegraded RNA. In some instances, the nucleic acid sequence comprises amicroRNA or portion thereof. In some instances, the nucleic acidsequence comprises an RNA molecule or a fragmented RNA molecule (RNAfragments) selected from: a microRNA (miRNA), a pre-miRNA, a pri-miRNA,a mRNA, a pre-mRNA, a viral RNA, a viroid RNA, a virusoid RNA, circularRNA (circRNA), a ribosomal RNA (rRNA), a transfer RNA (tRNA), apre-tRNA, a long non-coding RNA (ncRNA), a small nuclear RNA (snRNA), acirculating RNA, a cell-free RNA, an exosomal RNA, a vector-expressedRNA, an RNA transcript, a synthetic RNA, and combinations thereof.

Nucleic acid-based detection techniques that may be useful for themethods herein include quantitative polymerase chain reaction (qPCR),gel electrophoresis, immunochemistry, in situ hybridization such asfluorescent in situ hybridization (FISH), cytochemistry, and nextgeneration sequencing. In some embodiments, the methods involve TaqMan™qPCR, which involves a nucleic acid amplification reaction with aspecific primer pair, and hybridization of the amplified nucleic acidswith a hydrolysable probe specific to a target nucleic acid.

In some instances, the methods involve hybridization and/oramplification assays that include, but are not limited to, Southern orNorthern analyses, polymerase chain reaction analyses, and probe arrays.Non-limiting amplification reactions include, but are not limited to,qPCR, self-sustained sequence replication, transcriptional amplificationsystem, Q-Beta Replicase, rolling circle replication, or any othernucleic acid amplification known in the art. As discussed, reference toqPCR herein includes use of TaqMan™ methods. An additional exemplaryhybridization assay includes the use of nucleic acid probes conjugatedor otherwise immobilized on a bead, multi-well plate, or othersubstrate, wherein the nucleic acid probes are configured to hybridizewith a target nucleic acid sequence of a genotype provided herein. Anon-limiting method is one employed in Anal Chem. 2013 Feb. 5;85(3):1932-9.

In some embodiments, detecting the presence or absence of a genotypecomprises sequencing genetic material from the subject. Sequencing canbe performed with any appropriate sequencing technology, including butnot limited to single-molecule real-time (SMRT) sequencing, Polonysequencing, sequencing by ligation, reversible terminator sequencing,proton detection sequencing, ion semiconductor sequencing, nanoporesequencing, electronic sequencing, pyrosequencing, Maxam-Gilbertsequencing, chain termination (e.g., Sanger) sequencing, +S sequencing,or sequencing by synthesis. Sequencing methods also includenext-generation sequencing, e.g., modern sequencing technologies such asIllumina sequencing (e.g., Solexa), Roche 454 sequencing, Ion torrentsequencing, and SOLiD sequencing. In some cases, next-generationsequencing involves high-throughput sequencing methods. Additionalsequencing methods available to one of skill in the art may also beemployed.

In some instances, a number of nucleotides that are sequenced are atleast 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100, 150, 200, 300, 400,500, 2000, 4000, 6000, 8000, 10000, 20000, 50000, 100000, or more than100000 nucleotides. In some instances, the number of nucleotidessequenced is in a range of about 1 to about 100000 nucleotides, about 1to about 10000 nucleotides, about 1 to about 1000 nucleotides, about 1to about 500 nucleotides, about 1 to about 300 nucleotides, about 1 toabout 200 nucleotides, about 1 to about 100 nucleotides, about 5 toabout 100000 nucleotides, about 5 to about 10000 nucleotides, about 5 toabout 1000 nucleotides, about 5 to about 500 nucleotides, about 5 toabout 300 nucleotides, about 5 to about 200 nucleotides, about 5 toabout 100 nucleotides, about 10 to about 100000 nucleotides, about 10 toabout 10000 nucleotides, about 10 to about 1000 nucleotides, about 10 toabout 500 nucleotides, about 10 to about 300 nucleotides, about 10 toabout 200 nucleotides, about 10 to about 100 nucleotides, about 20 toabout 100000 nucleotides, about 20 to about 10000 nucleotides, about 20to about 1000 nucleotides, about 20 to about 500 nucleotides, about 20to about 300 nucleotides, about 20 to about 200 nucleotides, about 20 toabout 100 nucleotides, about 30 to about 100000 nucleotides, about 30 toabout 10000 nucleotides, about 30 to about 1000 nucleotides, about 30 toabout 500 nucleotides, about 30 to about 300 nucleotides, about 30 toabout 200 nucleotides, about 30 to about 100 nucleotides, about 50 toabout 100000 nucleotides, about 50 to about 10000 nucleotides, about 50to about 1000 nucleotides, about 50 to about 500 nucleotides, about 50to about 300 nucleotides, about 50 to about 200 nucleotides, or about 50to about 100 nucleotides.

Exemplary probes comprise a nucleic acid sequence of at least 10contiguous nucleic acids provided in any one of SEQ ID NOS: 1-48, or57-59, including the nucleobase indicated with a non-nucleobase letter(e.g., R, N, S), or a reverse complement thereof. In some instances, theprobes may be used to detect the polymorphisms provided in Table 1,wherein the probe comprises a nucleic acid sequence of at least 10contiguous nucleic acids provided in a corresponding SEQ ID NO orreverse complement thereof, the 10 contiguous nucleic acids comprisingthe “risk allele” also provided in Table 1 at a nucleoposition indicatedwith the non-nucleobase letter, or reverse complement thereof. In someembodiments, the probe comprises at least 70%, 80%, 85%, 90%, 91%, 92%,93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to any one of SEQID NOS: 1-48, or 57-59, or its reverse complement. In some instances,forward and reverse primers are used to amplify the target nucleic acidsequence. Forward and reverse primers may comprise a nucleic acidsequence flanking the risk allele provided in Table 1 corresponding tothe nucleic acid sequence provided in any one of SEQ ID NOS: 1-48, or57-59, or a reverse complement thereof.

Examples of molecules that are utilized as probes include, but are notlimited to, RNA and DNA. In some embodiments, the term “probe” withregards to nucleic acids, refers to any molecule that is capable ofselectively binding to a specifically intended target nucleic acidsequence. In some instances, probes are specifically designed to belabeled, for example, with a radioactive label, a fluorescent label, anenzyme, a chemiluminescent tag, a colorimetric tag, or other labels ortags that are known in the art. In some instances, the fluorescent labelcomprises a fluorophore. In some instances, the fluorophore is anaromatic or heteroaromatic compound. In some instances, the fluorophoreis a pyrene, anthracene, naphthalene, acridine, stilbene, benzoxazole,indole, benzindole, oxazole, thiazole, benzothiazole, canine,carbocyanine, salicylate, anthranilate, xanthenes dye, coumarin.Exemplary xanthene dyes include, e.g., fluorescein and rhodamine dyes.Fluorescein and rhodamine dyes include, but are not limited to6-carboxyfluorescein (FAM),2′7′-dimethoxy-4′5′-dichloro-6-carboxyfluorescein (JOE),tetrachlorofluorescein (TET), 6-carboxyrhodamine (R6G), N,N,N;N′-tetramethyl-6-carboxyrhodamine (TAMRA), 6-carboxy-X-rhodamine (ROX).Suitable fluorescent probes also include the naphthylamine dyes thathave an amino group in the alpha or beta position. For example,naphthylamino compounds include 1-dimethylaminonaphthyl-5-sulfonate,1-anilino-8-naphthalene sulfonate and 2-p-toluidinyl-6-naphthalenesulfonate, 5-(2′-aminoethyl)aminonaphthalene-1-sulfonic acid (EDANS).Exemplary coumarins include, e.g., 3-phenyl-7-isocyanatocoumarin;acridines, such as 9-isothiocyanatoacridine and acridine orange;N-(p-(2-benzoxazolyl)phenyl) maleimide; cyanines, such as, e.g.,indodicarbocyanine 3 (Cy3), indodicarbocyanine 5 (Cy5),indodicarbocyanine 5.5 (Cy5.5),3-(-carboxy-pentyl)-3′-ethyl-5,5′-dimethyloxacarbocyanine (CyA); 1H, 5H,11H, 15H-Xantheno[2,3, 4-ij: 5,6, 7-i′j′]diquinolizin-18-ium, 9-[2 (or4)-[[[6-[2,5-dioxo-1-pyrrolidinyl)oxy]-6-oxohexyl]amino]sulfonyl]-4 (or2)-sulfophenyl]-2,3, 6,7, 12,13, 16,17-octahydro-inner salt (TR or TexasRed); or BODIPY™ dyes. In some cases, the probe comprises FAM as the dyelabel.

In some instances, primers and/or probes described herein for detectinga target nucleic acid are used in an amplification reaction. In someinstances, the amplification reaction is qPCR. An exemplary qPCR is amethod employing a TaqMan™ assay. Non-limiting examples of primer pairsuseful for detecting one or more polymorphisms described herein areprovided in Table 6, below.

TABLE 6 Exemplary Primer Sequences rsID Forward Primer Reverse PrimerWt_Probe_Hex Mut_Probe_FAM rs6478109 TGCTTCTGGAAGTGAAAGTGAGGTTCAAAATGACAG TG + C + AG + A + TG + C + AGG + TGG T AGGT + TG + GGA GGA (SEQ ID NO: 364101) (SEQ ID NO: 364111)(SEQ ID NO: 364121) (SEQ ID NO: 364131) rs1892231 GTCATCATCGCTTTCATGTTT TCA ATG CAC AT + T + TG + G + ATT TGG + C + A + TG AGA TTT AAG GAA + A AGGG + AA A GGG AA (SEQ ID NO: 364102) (SEQ ID NO: 364112)(SEQ ID NO: 364122) (SEQ ID NO: 364132) rs7935393 CTGGATGCTCACAGGTTTCCT AAG GAG ACT AG + A A + T + A + T + AG + AA + T + G TTT AGT TCT AAGCA + C A + AG GA C + C + A CAA (SEQ ID NO: 364103) (SEQ ID NO: 364113)(SEQ ID NO: 364123) (SEQ ID NO: 364133) rs7278257 AGTCCCTGTTCTGAATCCATGGGGAACGTTGTGGCA TC + C + TA + G + T + C + C TA + G + TCT GC + G + A TA G + GA TA (SEQ ID NO: 364104) (SEQ ID NO: 364114)(SEQ ID NO: 364124) (SEQ ID NO: 364134) rs2070557 CTT TTT GTC TCCCGG CAG CCA GAC CGG GC + A + C + TCG GGC + TC + A TAC CTC AGA GG AGG TAAAG C + TC GC + T C (SEQ ID NO: 364105) (SEQ ID NO: 364115)(SEQ ID NO: 364125) (SEQ ID NO: 364135) rs9806914 ATAAGAACCTCTGCTGCAACAGAGGCAGTATAGCAC A + GT + GAT AGT GAT T + G + CA AG T + G + A + CT + CG + CTC AA (SEQ ID NO: 364106) (SEQ ID NO: 364116) AA(SEQ ID NO: 364136) (SEQ ID NO: 364126) rs16901748 TTGGGAATCAGATAGGTGATC AAG TCA CAA C + CA TTA A + C + C ATT CA CTG CCA GA A + A + G + T +AA + A + T + T + (SEQ ID NO: 364107) (SEQ ID NO: 364117) CA + GA C AGA(SEQ ID NO: 164127) (SEQ ID NO: 364137) rs56124762 AAA CAG GAA CAGGCTCTGCCTTCACATTTC TAG + T + T + A + TAG T + T + A + GCT GGT TC TGA + G + C CCAT G + GC CCA (SEQ ID NO: 364108) (SEQ ID NO: 364118)(SEQ ID NO: 364128) (SEQ ID NO: 364138) rs2070558 CCAAGCCAGTCCCAGTAGAAT GAC CAG ATC AAG GAC + G + C AGG GAC + C + A + (SEQ ID NO: 364109)CAA ATG AGG TGA C + TGA (SEQ ID NO: 364119) (SEQ ID NO: 364129)(SEQ ID NO: 364139) rs2070561 TTG GCA AGG TTT GTC CCC TGG TCTCGG T + G + C + CGG TGC + C + TC CAG GTT TG CCC TGT C T + TC GTC C GTC C(SEQ ID NO: 364110) (SEQ ID NO: 364120) (SEQ ID NO: 364130)(SEQ ID NO: 364140)“Wt_Probe_Hex” and “Mut_Probe_FAM” mean “Wild type probes tagged withHEX reporter dye” and “Mut_probe_tagged with FAM reporter dye”,respectively. “+” stands for LNA bases (Locked nucleotides), which areanalogues that are modified at 2′-O, 4′-C and form a bridge. This bridgeresults in restricted base pairing giving room to adjust the Tm asneeded between the probes. Thus, +A, +T, +C or +G signify A, T, G or Cbases are added on the modified backbone.

In some instances, qPCR comprises using an intercalating dye. Examplesof intercalating dyes include SYBR green I, SYBR green II, SYBR gold,ethidium bromide, methylene blue, Pyronin Y, DAPI, acridine orange, BlueView or phycoerythrin. In some instances, the intercalating dye is SYBR.

In some instances, a number of amplification cycles for detecting atarget nucleic acid in an amplification assay is about 5 to about 30cycles. In some instances, the number of amplification cycles fordetecting a target nucleic acid is at least about 5 cycles. In someinstances, the number of amplification cycles for detecting a targetnucleic acid is at most about 30 cycles. In some instances, the numberof amplification cycles for detecting a target nucleic acid is about 5to about 10, about 5 to about 15, about 5 to about 20, about 5 to about25, about 5 to about 30, about 10 to about 15, about 10 to about 20,about 10 to about 25, about 10 to about 30, about 15 to about 20, about15 to about 25, about 15 to about 30, about 20 to about 25, about 20 toabout 30, or about 25 to about 30 cycles.

In one aspect, the methods provided herein for determining the presence,absence, and/or quantity of a nucleic acid sequence from a particulargenotype comprise an amplification reaction such as qPCR. In anexemplary method, genetic material is obtained from a sample of asubject, e.g., a sample of blood or serum. In certain embodiments wherenucleic acids are extracted, the nucleic acids are extracted using anytechnique that does not interfere with subsequent analysis. In certainembodiments, this technique uses alcohol precipitation using ethanol,methanol, or isopropyl alcohol. In certain embodiments, this techniqueuses phenol, chloroform, or any combination thereof. In certainembodiments, this technique uses cesium chloride. In certainembodiments, this technique uses sodium, potassium or ammonium acetateor any other salt commonly used to precipitate DNA. In certainembodiments, this technique utilizes a column or resin based nucleicacid purification scheme such as those commonly sold commercially, onenon-limiting example would be the GenElute Bacterial Genomic DNA Kitavailable from Sigma Aldrich. In certain embodiments, after extractionthe nucleic acid is stored in water, Tris buffer, or Tris-EDTA bufferbefore subsequent analysis. In an exemplary embodiment, the nucleic acidmaterial is extracted in water. In some cases, extraction does notcomprise nucleic acid purification.

In the exemplary qPCR assay, the nucleic acid sample is combined withprimers and probes specific for a target nucleic acid that may or maynot be present in the sample, and a DNA polymerase. An amplificationreaction is performed with a thermal cycler that heats and cools thesample for nucleic acid amplification, and illuminates the sample at aspecific wavelength to excite a fluorophore on the probe and detect theemitted fluorescence. For TaqMan™ methods, the probe may be ahydrolysable probe comprising a fluorophore and quencher that ishydrolyzed by DNA polymerase when hybridized to a target nucleic acid.In some cases, the presence of a target nucleic acid is determined whenthe number of amplification cycles to reach a threshold value is lessthan 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, or 20 cycles.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 1 comprising a non-reference alleleat nucleoposition 501 within SEQ ID NO: 1. In some embodiments, thetarget nucleic acid is at least 10 contiguous nucleic acid molecules ofSEQ ID NO: 1 comprising a “G” or an “A” allele at nucleoposition 501within SEQ ID NO: 1. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising a “G” or an “A” allele atnucleoposition 501 within SEQ ID NO: 1 is sufficient to detect thepolymorphism at rs11897732.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 2 comprising non-reference alleleat nucleoposition 501 within SEQ ID NO: 2. In some embodiments, thetarget nucleic acid is at least 10 contiguous nucleic acid molecules ofSEQ ID NO: 2 comprising an “A” or a “G” allele at nucleoposition 501within SEQ ID NO: 2. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising an “A” or a “G” allele atnucleoposition 501 within SEQ ID NO: 2 is sufficient to detect thepolymorphism at rs6740739.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 3 comprising a non-reference alleleat nucleoposition 501 within SEQ ID NO: 3. In some embodiments, thetarget nucleic acid is at least 10 contiguous nucleic acid molecules ofSEQ ID NO: 3 comprising a “G” or a “C” allele at nucleoposition 501within SEQ ID NO: 3. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising a “G” or a “C” allele atnucleoposition 501 within SEQ ID NO: 3 is sufficient to detect thepolymorphism at rs17796285.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 4 comprising a non-reference alleleat nucleoposition 501 within SEQ ID NO: 4. In some embodiments, thetarget nucleic acid is at least 10 contiguous nucleic acid molecules ofSEQ ID NO: 4 comprising a “C” or an “A” allele at nucleoposition 501within SEQ ID NO: 4. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising a “C” or an “A” allele atnucleoposition 501 within SEQ ID NO: 4 is sufficient to detect thepolymorphism at rs7935393.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 5 comprising a non-reference alleleat nucleoposition 501 within SEQ ID NO: 5. In some embodiments, thetarget nucleic acid is at least 10 contiguous nucleic acid molecules ofSEQ ID NO: 5 comprising a “G” or an “A” allele at nucleoposition 501within SEQ ID NO: 5. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising a “G” of an “A” allele atnucleoposition 501 within SEQ ID NO: 5 is sufficient to detect thepolymorphism at rs12934476.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 6 comprising a non-reference alleleat nucleoposition 501 within SEQ ID NO: 6. In some embodiments, thetarget nucleic acid is at least 10 contiguous nucleic acid molecules ofSEQ ID NO: 6 comprising an “A” or a “C” allele at nucleoposition 501within SEQ ID NO: 6. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising an “A” or a “C” allele atnucleoposition 501 within SEQ ID NO: 6 is sufficient to detect thepolymorphism at rs12457255.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 7 comprising a non-reference alleleat nucleoposition 501 within SEQ ID NO: 7. In some embodiments, thetarget nucleic acid is at least 10 contiguous nucleic acid molecules ofSEQ ID NO: 7 comprising an “A” or a “T” allele at nucleoposition 501within SEQ ID NO: 7. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising an “A” or a “T” allele atnucleoposition 501 within SEQ ID NO: 7 is sufficient to detect thepolymorphism at rs2070557.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 8 comprising a non-reference alleleat nucleoposition 501 within SEQ ID NO: 8. In some embodiments, thetarget nucleic acid is at least 10 contiguous nucleic acid molecules ofSEQ ID NO: 8 comprising an “A” or a “G” allele at nucleoposition 501within SEQ ID NO: 8. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising an “A” or “G” allele atnucleoposition 501 within SEQ ID NO: 8 is sufficient to detect thepolymorphism at rs4246905.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 9 comprising a non-reference alleleat nucleoposition 501 within SEQ ID NO: 9. In some embodiments, thetarget nucleic acid is at least 10 contiguous nucleic acid molecules ofSEQ ID NO: 9 comprising an “A” or a “G” allele at nucleoposition 501within SEQ ID NO: 9. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising an “A” or a “G” allele atnucleoposition 501 within SEQ ID NO: 9 is sufficient to detect thepolymorphism at rs10974900.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 10 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 10. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 10 comprising a “C” or an “A” allele at nucleoposition 501within SEQ ID NO: 10. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising a “C” or an “A” allele atnucleoposition 501 within SEQ ID NO: 10 is sufficient to detect thepolymorphism at rs12434976.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 11 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 11. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 11 comprising an “A” or a “C” allele at nucleoposition 501within SEQ ID NO: 11. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising an “A” or a “C” allele atnucleoposition 501 within SEQ ID NO: 11 is sufficient to detect thepolymorphism at rs16901748.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 12 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 12. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 12 comprising an “A” or a “G” allele at nucleoposition 501within SEQ ID NO: 12. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising an “A” or a “G” allele atnucleoposition 501 within SEQ ID NO: 12 is sufficient to detect thepolymorphism at rs2815844.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 13 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 13. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 13 comprising a “G” or an “A” allele at nucleoposition 501within SEQ ID NO: 13. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising a “G” or an “A” allele atnucleoposition 501 within SEQ ID NO: 13 is sufficient to detect thepolymorphism at rs889702.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 14 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 14. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 14 comprising a “C” or an “A” allele at nucleoposition 501within SEQ ID NO: 14. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising a “C” or an “A” allele atnucleoposition 501 within SEQ ID NO: 14 is sufficient to detect thepolymorphism at rs2409750.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 15 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 15. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 15 comprising an “A” or a “G” allele at nucleoposition 501within SEQ ID NO: 15. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising an “A” or “G” allele atnucleoposition 501 within SEQ ID NO: 15 is sufficient to detect thepolymorphism at rs1541020.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 16 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 16. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 16 comprising a “T” or an “A” allele at nucleoposition 501within SEQ ID NO: 16. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising a “T” or an “A” allele atnucleoposition 501 within SEQ ID NO: 16 is sufficient to detect thepolymorphism at rs4942248.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 17 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 17. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 17 comprising a “G” or an “A” allele at nucleoposition 501within SEQ ID NO: 17. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising a “G” or an “A” allele atnucleoposition 501 within SEQ ID NO: 17 is sufficient to detect thepolymorphism at rs12934476.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 18 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 18. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 18 comprising an “A” or a “C” allele at nucleoposition 501within SEQ ID NO: 18. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising an “A” or a “C” allele atnucleoposition 501 within SEQ ID NO: 18 is sufficient to detect thepolymorphism at rs12457255.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 19 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 19. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 19 comprising an “A” or a “G” allele at nucleoposition 501within SEQ ID NO: 19. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising an “A” or a “G” allele atnucleoposition 501 within SEQ ID NO: 19 is sufficient to detect thepolymorphism at rs2297437.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 20 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 20. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 20 comprising a “G” or an “A” allele at nucleoposition 501within SEQ ID NO: 20. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising a “G” or an “A” allele atnucleoposition 501 within SEQ ID NO: 20 is sufficient to detect thepolymorphism at rs41309367.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 21 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 21. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 21 comprising an “A” or a “G” allele at nucleoposition 501within SEQ ID NO: 21. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising an “A” or a “G” allele atnucleoposition 501 within SEQ ID NO: 21 is sufficient to detect thepolymorphism at rs10733509.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 22 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 22. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 22 comprising a “G” or an “A” allele at nucleoposition 501within SEQ ID NO: 22. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising a “G” or an “A” allele atnucleoposition 501 within SEQ ID NO: 22 is sufficient to detect thepolymorphism at rs10750376.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 23 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 23. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 23 comprising a “G” or an “A” allele at nucleoposition 501within SEQ ID NO: 23. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising a “G” or an “A” allele atnucleoposition 501 within SEQ ID NO: 23 is sufficient to detect thepolymorphism at rs10932456.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 24 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 24. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 24 comprising an “A” or a “G” allele at nucleoposition 501within SEQ ID NO: 24. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising an “A” or a “G” allele atnucleoposition 501 within SEQ ID NO: 24 is sufficient to detect thepolymorphism at rs1326860.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 25 comprising a “G” or an “A”allele at nucleoposition 501 within SEQ ID NO: 25. In some embodiments,detecting the at least 10 contiguous nucleic acid molecules comprising a“G” or an “A” allele at nucleoposition 501 within SEQ ID NO: 25 issufficient to detect the polymorphism at rs1528663.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 26 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 26. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 26 comprising a “C” or an “A” allele at nucleoposition 501within SEQ ID NO: 26. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising a “C” or an “A” allele atnucleoposition 501 within SEQ ID NO: 26 is sufficient to detect thepolymorphism at rs1892231.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 27 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 27. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 27 comprising a “G” or an “A” allele at nucleoposition 501within SEQ ID NO: 27. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising a “G” or an “A” allele atnucleoposition 501 within SEQ ID NO: 27 is sufficient to detect thepolymorphism at rs951279.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 28 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 28. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 28 comprising an “A” or a “G” allele at nucleoposition 501within SEQ ID NO: 28. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising an “A” or a “G” allele atnucleoposition 501 within SEQ ID NO: 28 is sufficient to detect thepolymorphism at rs9806914.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 29 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 29. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 29 comprising a “C” or an “A” allele at nucleoposition 501within SEQ ID NO: 29. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising a “C” or an “A” allele atnucleoposition 501 within SEQ ID NO: 29 is sufficient to detect thepolymorphism at rs7935393.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 30 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 30. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 30 comprising a “G” or a “C” allele at nucleoposition 501within SEQ ID NO: 30. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising a “G” or a “C” allele atnucleoposition 501 within SEQ ID NO: 30 is sufficient to detect thepolymorphism at rs1690492.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 31 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 31. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 31 comprising a “G” or an “A” allele at nucleoposition 501within SEQ ID NO: 31. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising a “G” or an “A” allele atnucleoposition 501 within SEQ ID NO: 31 is sufficient to detect thepolymorphism at rs420726.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 32 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 32. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 32 comprising a “T” or an “A” allele at nucleoposition 501within SEQ ID NO: 32. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising a “T” of an “A” allele atnucleoposition 501 within SEQ ID NO: 32 is sufficient to detect thepolymorphism at rs7759385.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 33 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 33. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 33 comprising an “A” or a “G” allele at nucleoposition 501within SEQ ID NO: 33. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising an “A” or a “G” allele atnucleoposition 501 within SEQ ID NO: 33 is sufficient to detect thepolymorphism at rs10974900.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 34 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 34. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 34 comprising an “A” or a “G” allele at nucleoposition 501within SEQ ID NO: 34. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising an “A” or a “G” allele atnucleoposition 501 within SEQ ID NO: 34 is sufficient to detect thepolymorphism at rs1326860.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 35 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 35. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 35 comprising a “C” or a “G” allele at nucleoposition 501within SEQ ID NO: 35. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising a “C” or a “G” allele atnucleoposition 501 within SEQ ID NO: 35 is sufficient to detect thepolymorphism at rs2548147.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 36 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 36. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 36 comprising an “A” or a “G” allele at nucleoposition 501within SEQ ID NO: 36. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising an “A” of a “G” allele atnucleoposition 501 within SEQ ID NO: 36 is sufficient to detect thepolymorphism at rs2815844.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 37 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 37. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 37 comprising a “G” or an “A” allele at nucleoposition 501within SEQ ID NO: 37. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising a “G” or an “A” allele atnucleoposition 501 within SEQ ID NO: 37 is sufficient to detect thepolymorphism at rs889702.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 38 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 38. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 38 comprising an “A” or a “G” allele at nucleoposition 501within SEQ ID NO: 38. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising an “A” or a “G” allele atnucleoposition 501 within SEQ ID NO: 38 is sufficient to detect thepolymorphism at rs9806914.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 39 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 39. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 39 comprising an “A” or a “G” allele at nucleoposition 501within SEQ ID NO: 39. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising an “A” or a “G” allele atnucleoposition 501 within SEQ ID NO: 39 is sufficient to detect thepolymorphism at rs6478109.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 40 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 40. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 40 comprising a “C” or a “G” allele at nucleoposition 501within SEQ ID NO: 40. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising a “C” or a “G” allele atnucleoposition 501 within SEQ ID NO: 40 is sufficient to detect thepolymorphism at rs7278257.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 41 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 41. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 41 comprising an “A” or a “G” allele at nucleoposition 501within SEQ ID NO: 41. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising an “A” or a “G” allele atnucleoposition 501 within SEQ ID NO: 41 is sufficient to detect thepolymorphism at rs11221332.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 57 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 57. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 57 comprising an “A” or a “G” allele at nucleoposition 501within SEQ ID NO: 57. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising an “A” or a “G” allele atnucleoposition 501 within SEQ ID NO: 57 is sufficient to detect thepolymorphism at rs56124762.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 58 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 58. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 58 comprising an “A” or a “G” allele at nucleoposition 501within SEQ ID NO: 58. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising an “A” or a “G” allele atnucleoposition 501 within SEQ ID NO: 58 is sufficient to detect thepolymorphism at rs2070558.

In some embodiments, the target nucleic acid is at least 10 contiguousnucleic acid molecules of SEQ ID NO: 59 comprising a non-referenceallele at nucleoposition 501 within SEQ ID NO: 59. In some embodiments,the target nucleic acid is at least 10 contiguous nucleic acid moleculesof SEQ ID NO: 59 comprising an “T” or a “C” allele at nucleoposition 501within SEQ ID NO: 59. In some embodiments, detecting the at least 10contiguous nucleic acid molecules comprising an “T” or a “C” allele atnucleoposition 501 within SEQ ID NO: 59 is sufficient to detect thepolymorphism at rs2070561.

In some embodiments, one target nucleic acid (e.g., a polymorphism) isdetected with the methods disclosed herein. In some embodiments, atleast 2, 3, 4, 5, 6, 7, 8, 9, or 10 target nucleic acids are detected.In some embodiments, the at least 2, 3, 4, 5, 6, 7, 8, 9, or 10 targetnucleic acids are detected in a single multiplexed assay. In someembodiments, when 4 target nucleic acids are detected in a sample fromsubject, 4 unique 3-polymorphism combinations are measured. In anon-limiting example, a sample (e.g., blood or plasma) obtained from asubject is contacted by 4 primer pairs, each primer pair individuallyadapted to amplify rs6487109, rs56124762, rs1892231, and rs16901748,respectively. A positive, negative, or indeterminate TNFSF15 profile maydepend, at least in part, on which of the 3-polymorphism combinations isdetected in the sample, and/or whether the genotype is heterozygous orhomozygous for the polymorphism. In this example, assaying 4polymorphism means a total of 4 unique 3-polymorphisms may be detectedin the patient sample, which are rs6478109, rs56124762, rs1892231;rs6478109, rs56124762, rs16901748; rs6478109, rs1892231, rs16901748; andrs56124762, rs1892231, rs16901748. Each polymorphism detected may beheterozygous or homozygous.

To practice the methods and systems provided herein, genetic materialmay be extracted from a sample obtained from a subject, e.g., a sampleof blood or serum. In certain embodiments where nucleic acids areextracted, the nucleic acids are extracted using any technique that doesnot interfere with subsequent analysis. In certain embodiments, thistechnique uses alcohol precipitation using ethanol, methanol orisopropyl alcohol. In certain embodiments, this technique uses phenol,chloroform, or any combination thereof. In certain embodiments, thistechnique uses cesium chloride. In certain embodiments, this techniqueuses sodium, potassium or ammonium acetate or any other salt commonlyused to precipitate DNA. In certain embodiments, this technique utilizesa column or resin based nucleic acid purification scheme such as thosecommonly sold commercially, one non-limiting example would be theGenElute Bacterial Genomic DNA Kit available from Sigma Aldrich. Incertain embodiments, after extraction the nucleic acid is stored inwater, Tris buffer, or Tris-EDTA buffer before subsequent analysis. Inan exemplary embodiment, the nucleic acid material is extracted inwater. In some cases, extraction does not comprise nucleic acidpurification. In certain embodiments, RNA may be extracted from cellsusing RNA extraction techniques including, for example, using acidphenol/guanidine isothiocyanate extraction (RNAzol B; Biogenesis),RNeasy RNA preparation kits (Qiagen) or PAXgene (PreAnalytix,Switzerland).

In some embodiments, methods of detecting a presence, absence, or levelof a target protein (e.g., biomarker) in the sample obtained from thesubject involve detecting protein activity or expression. In someembodiments, the target protein is TL1A, or a binding partner of TL1Asuch as Death Domain Receptor 3 (DcR3). A target protein may be detectedby use of an antibody-based assay, where an antibody specific to thetarget protein is utilized. In some embodiments, antibody-baseddetection methods utilize an antibody that binds to any region of targetprotein. An exemplary method of analysis comprises performing anenzyme-linked immunosorbent assay (ELISA). The ELISA assay may be asandwich ELISA or a direct ELISA. Another exemplary method of analysiscomprises a single molecule array, e.g., Simoa. Other exemplary methodsof detection include immunohistochemistry and lateral flow assay.Additional exemplary methods for detecting target protein include, butare not limited to, gel electrophoresis, capillary electrophoresis, highperformance liquid chromatography (HPLC), thin layer chromatography(TLC), hyperdiffusion chromatography, and the like, or variousimmunological methods such as fluid or gel precipitation reactions,immunodiffusion (single or double), immunoelectrophoresis,radioimmunoassay (RIA), immunofluorescent assays, and Western blotting.In some embodiments, antibodies, or antibody fragments, are used inmethods such as Western blots or immunofluorescence techniques to detectthe expressed proteins. The antibody or protein can be immobilized on asolid support for Western blots and immunofluorescence techniques.Suitable solid phase supports or carriers include any support capable ofbinding an antigen or an antibody. Exemplary supports or carriersinclude glass, polystyrene, polypropylene, polyethylene, dextran, nylon,amylases, natural and modified celluloses, polyacrylamides, gabbros, andmagnetite.

In some cases, a target protein may be detected by detecting bindingbetween the target protein and a binding partner of the target protein.Non-limiting examples of binding partners to TL1A include DcR3, andTumor necrosis factor receptor superfamily member 25 (TNR25). Exemplarymethods of analysis of protein-protein binding comprise performing anassay in vivo or in vitro, or ex vivo. In some instances, the method ofanalysis comprises an assay such as a co-immunoprecipitation (co-IP),pull-down, crosslinking protein interaction analysis, labeled transferprotein interaction analysis, or Far-western blot analysis, FRET basedassay, including, for example FRET-FLIM, a yeast two-hybrid assay, BiFC,or split luciferase assay.

Disclosed herein are methods of detecting a presence or a level of oneor more serological markers in a sample obtained from a subject. In someembodiments, the one or more serological markers comprisesanti-Saccharomyces cerevisiae antibody (ASCA), an anti-neutrophilcytoplasmic antibody (ANCA), antibody against E. coli outer membraneporin protein C (anti-OmpC), anti-chitin antibody, pANCA antibody,anti-I2 antibody, and anti-Cbir1 flagellin antibody. In someembodiments, the antibodies comprises immunoglobulin A (IgA),immunoglobulin G (IgG), immunoglobulin E (IgE), or immunoglobulin M(IgM), immunoglobulin D (IgD), or a combination thereof. Any suitablemethod for detecting a target protein or biomarker disclosed herein maybe used to detect a presence, absence, or level of a serological marker.In some embodiments, the presence or the level of the one or moreserological markers is detectedusing an enzyme-linked immunosorbentassay (ELISA), a single molecule array (Simoa), immunohistochemistry,internal transcribed spacer (ITS) sequencing, or any combinationthereof. In some embodiments, the ELISA is a fixed leukocyte ELISA. Insome embodiments, the ELISA is a fixed neutrophil ELISA. A fixedleukocyte or neutrophil ELISA may be useful for the detection of certainserological markers, such as those described in Saxon et al., A distinctsubset of antineutrophil cytoplasmic antibodies is associated withinflammatory bowel disease, J. Allergy Clin. Immuno. 86:2; 202-210(August 1990). In some embodiments, ELISA units (EU) are used to measurepositivity of a presence or level of a serological marker (e.g.,seropositivity), which reflects a percentage of a standard or referencevalue. In some embodiments, the standard comprises pooled sera obtainedfrom well-characterized patient population (e.g., diagnosed with thesame disease or condition the subject has, or is suspected of having)reported as being seropositive for the serological marker of interest.In some embodiments, the control or reference value comprises 10, 20,30, 40, 50, 60, 70, 80, 90, or 100 EU. In some instances, a quartile sumscores are calculated using, for example, the methods reported inLanders C J, Cohavy O, Misra R. et al., Selected loss of toleranceevidenced by Crohn's disease-associated immune responses to auto- andmicrobial antigens. Gastroenterology (2002)123:689-699.

Methods of Treatment

Disclosed herein are methods of treating a disease or condition, or asymptom of the disease or condition, in a subject, comprisingadministrating of therapeutic effective amount of one or moretherapeutic agents to the subject. In some embodiments, the one or moretherapeutic agents is administered to the subject alone (e.g.,standalone therapy). In some embodiments, the one or more therapeuticagents is administered in combination with an additional agent. In someembodiments, the therapeutic agent is a first-line therapy for thedisease or condition. In some embodiments, the therapeutic agent is asecond-line, third-line, or fourth-line therapy, for the disease orcondition.

Therapeutic Agents

Aspects provided herein are methods of treating an inflammatory,fibrostenotic, or fibrotic disease or condition in a subject byadministering a therapeutically effective amount of an inhibitor of TNFSuperfamily Member 15 (TL1A) activity or expression to the subject,provided a genotype is detected in a sample obtained from the subject.In some cases, the TL1A protein comprises an amino acid sequenceprovided in any one of SEQ ID NOS: 50-52. In some cases, the TL1Aprotein comprises an amino acid sequence that is at least or about 70%,80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, or 99% identical toany one of SEQ ID NOS: 50-52. In some embodiments, the inhibitor of TL1Aactivity or expression is effective to inhibit TL1A-DR3 binding. In someembodiments, the inhibitor of TL1A activity or expression comprises anallosteric modulator of TL1A. An allosteric modulator of TL1A mayindirectly influence the effects TL1A on DR3, or TR6/DcR3 on TL1A orDR3. The inhibitor of TL1A activity or expression may be a directinhibitor or indirect inhibitor. Non-limiting examples of an inhibitorof TL1A expression include RNA to protein TL1A translation inhibitors,antisense oligonucleotides targeting the TNFSF15 mRNA (such as miRNAs,or siRNA), epigenetic editing (such as targeting the DNA-binding domainof TNFSF15, or post-translational modifications of histone tails and/orDNA molecules). Non-limiting examples of an inhibitor of TL1A activityinclude antagonists to the TL1A receptors, (DR3 and TR6/DcR3),antagonists to TL1A antigen, and antagonists to gene expression productsinvolved in TL1A mediated disease. Antagonists as disclosed herein, mayinclude, but are not limited to, an anti-TL1A antibody, ananti-TL1A-binding antibody fragment, or a small molecule. The smallmolecule may be a small molecule that binds to TL1A or DR3. Theanti-TL1A antibody may be monoclonal or polyclonal. The anti-TL1Aantibody may be humanized or chimeric. The anti-TL1A antibody may be afusion protein. The anti-TL1A antibody may be a blocking anti-TL1Aantibody. A blocking antibody blocks binding between two proteins, e.g.,a ligand and its receptor. Therefore, a TL1A blocking antibody includesan antibody that prevents binding of TL1A to DR3 and/or TR6/DcR3receptors. In a non-limiting example, the TL1A blocking antibody bindsto DR3. In another example, the TL1A blocking antibody binds to DcR3. Insome cases, the TL1A antibody is an anti-TL1A antibody that specificallybinds to TL1A. In some cases, the TL1A antibody specifically binds to anepitope of the TL1A protein provided in any one of SEQ ID NOS: 50-52. Insome cases, the TL1A protein comprises an amino acid sequence that is atleast or about 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%. 97%, 98%, or99% identical to any one of SEQ ID NOS: 50-52. The anti-TL1A antibodymay comprise one or more of the antibody sequences of Table 2A or Table2B. The anti-DR3 antibody may comprise an amino acid sequence that is atleast 85% identical to any one of SEQ ID NOS: 258-270 and an amino acidsequence that is at least 85% identical to any one of SEQ ID NOS:271-275. The anti-DR3 antibody may comprise an amino acid sequencecomprising the HCDR1, HCDR2, HCDR3 domains of any one of SEQ ID NOS:258-270 and the LCDR1, LCDR2, and LCDR3 domains of any one of SEQ IDNOS: 271-275.

In some embodiments, an anti-TL1A antibody comprises a heavy chaincomprising three complementarity-determining regions: HCDR1, HCDR2, andHCDR3; and a light chain comprising three complementarity-determiningregions: LCDR1, LCDR2, and LCDR3. In some embodiments, the anti-TL1Aantibody comprises a HCDR1 comprising SEQ ID NO: 109, a HCDR2 comprisingSEQ ID NO: 110, a HCDR3 comprising SEQ ID NO: 111, a LCDR1 comprisingSEQ ID NO: 112, a LCDR2 comprising SEQ ID NO: 113, and a LCDR3comprising SEQ ID NO: 114. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 115and a light chain (LC) variable domain comprising SEQ ID NO: 116.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprisingSEQ ID NO: 117, a HCDR2 comprising SEQ ID NO: 118, a HCDR3 comprisingSEQ ID NO: 119, a LCDR1 comprising SEQ ID NO: 120, a LCDR2 comprisingSEQ ID NO: 121, and a LCDR3 comprising SEQ ID NO: 122. In some cases,the anti-TL1A antibody comprises a heavy chain (HC) variable domaincomprising SEQ ID NO: 123 and a light chain (LC) variable domaincomprising SEQ ID NO: 124.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprisingSEQ ID NO: 125, a HCDR2 comprising SEQ ID NO: 126, a HCDR3 comprisingSEQ ID NO: 127, a LCDR1 comprising SEQ ID NO: 128, a LCDR2 comprisingSEQ ID NO: 129, and a LCDR3 comprising SEQ ID NO: 130. In some cases,the anti-TL1A antibody comprises a heavy chain (HC) variable domaincomprising SEQ ID NO: 131 and a light chain (LC) variable domaincomprising SEQ ID NO: 132.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprisingSEQ ID NO: 133, a HCDR2 comprising SEQ ID NO: 134, a HCDR3 comprisingSEQ ID NO: 135, a LCDR1 comprising SEQ ID NO: 139, a LCDR2 comprisingSEQ ID NO: 140, and a LCDR3 comprising SEQ ID NO: 141. In some cases,the anti-TL1A antibody comprises a HCDR1 comprising SEQ ID NO: 136, aHCDR2 comprising SEQ ID NO: 137, a HCDR3 comprising SEQ ID NO: 138, aLCDR1 comprising SEQ ID NO: 139, a LCDR2 comprising SEQ ID NO: 140, anda LCDR3 comprising SEQ ID NO: 141. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 142and a light chain (LC) variable domain comprising SEQ ID NO: 143. Insome cases, the anti-TL1A antibody comprises a heavy chain comprisingSEQ ID NO: 144. In some cases, the anti-TL1A antibody comprises a lightchain comprising SEQ ID NO: 145.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprisingSEQ ID NO: 146, a HCDR2 comprising SEQ ID NO: 147, a HCDR3 comprisingSEQ ID NO: 148, a LCDR1 comprising SEQ ID NO: 149, a LCDR2 comprisingSEQ ID NO: 150, and a LCDR3 comprising SEQ ID NO: 151. In some cases,the anti-TL1A antibody comprises a heavy chain (HC) variable domaincomprising SEQ ID NO: 152 and a light chain (LC) variable domaincomprising SEQ ID NO: 153.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprisingSEQ ID NO: 154, a HCDR2 comprising SEQ ID NO: 155, a HCDR3 comprisingSEQ ID NO: 156, a LCDR1 comprising SEQ ID NO: 157, a LCDR2 comprisingSEQ ID NO: 158, and a LCDR3 comprising SEQ ID NO: 159. In some cases,the anti-TL1A antibody comprises a heavy chain (HC) variable domaincomprising SEQ ID NO: 160 and a light chain (LC) variable domaincomprising SEQ ID NO: 161.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprisingSEQ ID NO: 162, a HCDR2 comprising SEQ ID NO: 164, a HCDR3 comprisingSEQ ID NO: 165, a LCDR1 comprising SEQ ID NO: 167, a LCDR2 comprisingSEQ ID NO: 169, and a LCDR3 comprising SEQ ID NO: 170. In some cases,the anti-TL1A antibody comprises a heavy chain (HC) variable domaincomprising SEQ ID NO: 171 and a light chain (LC) variable domaincomprising SEQ ID NO: 175. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 171and a light chain (LC) variable domain comprising SEQ ID NO: 176. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 171 and a light chain (LC) variable domaincomprising SEQ ID NO: 177. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 171and a light chain (LC) variable domain comprising SEQ ID NO: 178.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprisingSEQ ID NO: 162, a HCDR2 comprising SEQ ID NO: 164, a HCDR3 comprisingSEQ ID NO: 165, a LCDR1 comprising SEQ ID NO: 168, a LCDR2 comprisingSEQ ID NO: 169, and a LCDR3 comprising SEQ ID NO: 170. In some cases,the anti-TL1A antibody comprises a heavy chain (HC) variable domaincomprising SEQ ID NO: 171 and a light chain (LC) variable domaincomprising SEQ ID NO: 179. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 171and a light chain (LC) variable domain comprising SEQ ID NO: 180. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 171 and a light chain (LC) variable domaincomprising SEQ ID NO: 181. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 171and a light chain (LC) variable domain comprising SEQ ID NO: 182.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprisingSEQ ID NO: 162, a HCDR2 comprising SEQ ID NO: 164, a HCDR3 comprisingSEQ ID NO: 165, a LCDR1 comprising SEQ ID NO: 167, a LCDR2 comprisingSEQ ID NO: 169, and a LCDR3 comprising SEQ ID NO: 170. In some cases,the anti-TL1A antibody comprises a heavy chain (HC) variable domaincomprising SEQ ID NO: 172 and a light chain (LC) variable domaincomprising SEQ ID NO: 175. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 172and a light chain (LC) variable domain comprising SEQ ID NO: 176. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 172 and a light chain (LC) variable domaincomprising SEQ ID NO: 177. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 172and a light chain (LC) variable domain comprising SEQ ID NO: 178.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprisingSEQ ID NO: 162, a HCDR2 comprising SEQ ID NO: 164, a HCDR3 comprisingSEQ ID NO: 165, a LCDR1 comprising SEQ ID NO: 168, a LCDR2 comprisingSEQ ID NO: 169, and a LCDR3 comprising SEQ ID NO: 170. In some cases,the anti-TL1A antibody comprises a heavy chain (HC) variable domaincomprising SEQ ID NO: 172 and a light chain (LC) variable domaincomprising SEQ ID NO: 179. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 172and a light chain (LC) variable domain comprising SEQ ID NO: 180. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 172 and a light chain (LC) variable domaincomprising SEQ ID NO: 181. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 172and a light chain (LC) variable domain comprising SEQ ID NO: 182.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprisingSEQ ID NO: 163, a HCDR2 comprising SEQ ID NO: 164, a HCDR3 comprisingSEQ ID NO: 166, a LCDR1 comprising SEQ ID NO: 167, a LCDR2 comprisingSEQ ID NO: 169, and a LCDR3 comprising SEQ ID NO: 170. In some cases,the anti-TL1A antibody comprises a heavy chain (HC) variable domaincomprising SEQ ID NO: 173 and a light chain (LC) variable domaincomprising SEQ ID NO: 175. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 173and a light chain (LC) variable domain comprising SEQ ID NO: 176. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 173 and a light chain (LC) variable domaincomprising SEQ ID NO: 177. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 173and a light chain (LC) variable domain comprising SEQ ID NO: 178. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 173 and a light chain (LC) variable domaincomprising SEQ ID NO: 179. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 173and a light chain (LC) variable domain comprising SEQ ID NO: 180. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 173 and a light chain (LC) variable domaincomprising SEQ ID NO: 181. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 173and a light chain (LC) variable domain comprising SEQ ID NO: 182.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprisingSEQ ID NO: 163, a HCDR2 comprising SEQ ID NO: 164, a HCDR3 comprisingSEQ ID NO: 166, a LCDR1 comprising SEQ ID NO: 168, a LCDR2 comprisingSEQ ID NO: 169, and a LCDR3 comprising SEQ ID NO: 170. In some cases,the anti-TL1A antibody comprises a heavy chain (HC) variable domaincomprising SEQ ID NO: 174 and a light chain (LC) variable domaincomprising SEQ ID NO: 179. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 174and a light chain (LC) variable domain comprising SEQ ID NO: 180. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 174 and a light chain (LC) variable domaincomprising SEQ ID NO: 181. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 174and a light chain (LC) variable domain comprising SEQ ID NO: 182. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 174 and a light chain (LC) variable domaincomprising SEQ ID NO: 175. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 174and a light chain (LC) variable domain comprising SEQ ID NO: 176. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 174 and a light chain (LC) variable domaincomprising SEQ ID NO: 177. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 174and a light chain (LC) variable domain comprising SEQ ID NO: 178.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprisingSEQ ID NO: 183, a HCDR2 comprising SEQ ID NO: 184, a HCDR3 comprisingSEQ ID NO: 185, a LCDR1 comprising SEQ ID NO: 186, a LCDR2 comprisingSEQ ID NO: 187, and a LCDR3 comprising SEQ ID NO: 188. In some cases,the anti-TL1A antibody comprises a heavy chain (HC) variable domaincomprising SEQ ID NO: 189 and a light chain (LC) variable domaincomprising SEQ ID NO: 194. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 189and a light chain (LC) variable domain comprising SEQ ID NO: 195. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 189 and a light chain (LC) variable domaincomprising SEQ ID NO: 196. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 189and a light chain (LC) variable domain comprising SEQ ID NO: 197. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 190 and a light chain (LC) variable domaincomprising SEQ ID NO: 194. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 190and a light chain (LC) variable domain comprising SEQ ID NO: 195. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 190 and a light chain (LC) variable domaincomprising SEQ ID NO: 196. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 190and a light chain (LC) variable domain comprising SEQ ID NO: 197. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 191 and a light chain (LC) variable domaincomprising SEQ ID NO: 194. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 191and a light chain (LC) variable domain comprising SEQ ID NO: 195. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 191 and a light chain (LC) variable domaincomprising SEQ ID NO: 196. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 191and a light chain (LC) variable domain comprising SEQ ID NO: 197. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 192 and a light chain (LC) variable domaincomprising SEQ ID NO: 194. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 192and a light chain (LC) variable domain comprising SEQ ID NO: 195. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 192 and a light chain (LC) variable domaincomprising SEQ ID NO: 196. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 192and a light chain (LC) variable domain comprising SEQ ID NO: 197. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 193 and a light chain (LC) variable domaincomprising SEQ ID NO: 194. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 193and a light chain (LC) variable domain comprising SEQ ID NO: 195. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 193 and a light chain (LC) variable domaincomprising SEQ ID NO: 196. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 193and a light chain (LC) variable domain comprising SEQ ID NO: 197.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprisingSEQ ID NO: 198, a HCDR2 comprising SEQ ID NO: 199, a HCDR3 comprisingSEQ ID NO: 200, a LCDR1 comprising SEQ ID NO: 201, a LCDR2 comprisingSEQ ID NO: 202, and a LCDR3 comprising SEQ ID NO: 203. In some cases,the anti-TL1A antibody comprises a heavy chain (HC) variable domaincomprising SEQ ID NO: 204 and a light chain (LC) variable domaincomprising SEQ ID NO: 205. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 206and a light chain (LC) variable domain comprising SEQ ID NO: 207. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 208 and a light chain (LC) variable domaincomprising SEQ ID NO: 209. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 210and a light chain (LC) variable domain comprising SEQ ID NO: 211. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 212 and a light chain (LC) variable domaincomprising SEQ ID NO: 213. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 214and a light chain (LC) variable domain comprising SEQ ID NO: 215. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 216 and a light chain (LC) variable domaincomprising SEQ ID NO: 217. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 218and a light chain (LC) variable domain comprising SEQ ID NO: 219. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 220 and a light chain (LC) variable domaincomprising SEQ ID NO: 221. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 222and a light chain (LC) variable domain comprising SEQ ID NO: 223. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 224 and a light chain (LC) variable domaincomprising SEQ ID NO: 225. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 226and a light chain (LC) variable domain comprising SEQ ID NO: 227.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprisingSEQ ID NO: 228, a HCDR2 comprising SEQ ID NO: 229, a HCDR3 comprisingSEQ ID NO: 230, a LCDR1 comprising SEQ ID NO: 231, a LCDR2 comprisingSEQ ID NO: 232, and a LCDR3 comprising SEQ ID NO: 233. In some cases,the anti-TL1A antibody comprises a heavy chain (HC) variable domaincomprising SEQ ID NO: 234 and a light chain (LC) variable domaincomprising SEQ ID NO: 235.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprisingSEQ ID NO: 236, a HCDR2 comprising SEQ ID NO: 237, a HCDR3 comprisingSEQ ID NO: 238, a LCDR1 comprising SEQ ID NO: 239, a LCDR2 comprisingSEQ ID NO: 240, and a LCDR3 comprising SEQ ID NO: 241. In some cases,the anti-TL1A antibody comprises a heavy chain (HC) variable domaincomprising SEQ ID NO: 242 and a light chain (LC) variable domaincomprising SEQ ID NO: 243.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprisingSEQ ID NO: 246, a HCDR2 comprising SEQ ID NO: 247, a HCDR3 comprisingSEQ ID NO: 248, a LCDR1 comprising SEQ ID NO: 249, a LCDR2 comprisingSEQ ID NO: 250, and a LCDR3 comprising SEQ ID NO: 251. In some cases,the anti-TL1A antibody comprises a heavy chain (HC) variable domaincomprising SEQ ID NO: 244 and a light chain (LC) variable domaincomprising SEQ ID NO: 245. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 252and a light chain (LC) variable domain comprising SEQ ID NO: 253. Insome cases, the anti-TL1A antibody comprises a heavy chain (HC) variabledomain comprising SEQ ID NO: 254 and a light chain (LC) variable domaincomprising SEQ ID NO: 255. In some cases, the anti-TL1A antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 256and a light chain (LC) variable domain comprising SEQ ID NO: 257.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprisingSEQ ID NO: 276, a HCDR2 comprising SEQ ID NO: 277, a HCDR3 comprisingSEQ ID NO: 278, a LCDR1 comprising SEQ ID NO: 279, a LCDR2 comprisingSEQ ID NO: 280, and a LCDR3 comprising SEQ ID NO: 281. In some cases,the anti-TL1A antibody comprises a heavy chain (HC) variable domaincomprising SEQ ID NO: 282 and a light chain (LC) variable domaincomprising SEQ ID NO: 283.

In some embodiments, the anti-TL1A antibody comprises a HCDR1 comprisingSEQ ID NO: 284, a HCDR2 comprising SEQ ID NO: 285, a HCDR3 comprisingSEQ ID NO: 286, a LCDR1 comprising SEQ ID NO: 287, a LCDR2 comprisingSEQ ID NO: 288, and a LCDR3 comprising SEQ ID NO: 299. In some cases,the anti-TL1A antibody comprises a heavy chain (HC) variable domaincomprising SEQ ID NO: 290 and a light chain (LC) variable domaincomprising SEQ ID NO: 291.

In some embodiments, the anti-TL1A antibody is A100. In someembodiments, the anti-TL1A antibody is A101. In some embodiments, theanti-TL1A antibody is A102. In some embodiments, the anti-TL1A antibodyis A103. In some embodiments, the anti-TL1A antibody is A104. In someembodiments, the anti-TL1A antibody is A105. In some embodiments, theanti-TL1A antibody is A106. In some embodiments, the anti-TL1A antibodyis A107. In some embodiments, the anti-TL1A antibody is A108. In someembodiments, the anti-TL1A antibody is A109. In some embodiments, theanti-TL1A antibody is A110. In some embodiments, the anti-TL1A antibodyis A111. In some embodiments, the anti-TL1A antibody is A112. In someembodiments, the anti-TL1A antibody is A113. In some embodiments, theanti-TL1A antibody is A114. In some embodiments, the anti-TL1A antibodyis A115. In some embodiments, the anti-TL1A antibody is A116. In someembodiments, the anti-TL1A antibody is A117. In some embodiments, theanti-TL1A antibody is A118. In some embodiments, the anti-TL1A antibodyis A119. In some embodiments, the anti-TL1A antibody is A120. In someembodiments, the anti-TL1A antibody is A121. In some embodiments, theanti-TL1A antibody is A122. In some embodiments, the anti-TL1A antibodyis A123. In some embodiments, the anti-TL1A antibody is A124. In someembodiments, the anti-TL1A antibody is A125. In some embodiments, theanti-TL1A antibody is A126. In some embodiments, the anti-TL1A antibodyis A127. In some embodiments, the anti-TL1A antibody is A128. In someembodiments, the anti-TL1A antibody is A129. In some embodiments, theanti-TL1A antibody is A130. In some embodiments, the anti-TL1A antibodyis A131. In some embodiments, the anti-TL1A antibody is A132. In someembodiments, the anti-TL1A antibody is A133. In some embodiments, theanti-TL1A antibody is A134. In some embodiments, the anti-TL1A antibodyis A135. In some embodiments, the anti-TL1A antibody is A136. In someembodiments, the anti-TL1A antibody is A137. In some embodiments, theanti-TL1A antibody is A138. In some embodiments, the anti-TL1A antibodyis A139. In some embodiments, the anti-TL1A antibody is A140. In someembodiments, the anti-TL1A antibody is A141. In some embodiments, theanti-TL1A antibody is A142. In some embodiments, the anti-TL1A antibodyis A143. In some embodiments, the anti-TL1A antibody is A144. In someembodiments, the anti-TL1A antibody is A145. In some embodiments, theanti-TL1A antibody is A146. In some embodiments, the anti-TL1A antibodyis A147. In some embodiments, the anti-TL1A antibody is A148. In someembodiments, the anti-TL1A antibody is A149. In some embodiments, theanti-TL1A antibody is A150. In some embodiments, the anti-TL1A antibodyis A151. In some embodiments, the anti-TL1A antibody is A152. In someembodiments, the anti-TL1A antibody is A153. In some embodiments, theanti-TL1A antibody is A154. In some embodiments, the anti-TL1A antibodyis A155. In some embodiments, the anti-TL1A antibody is A156. In someembodiments, the anti-TL1A antibody is A157. In some embodiments, theanti-TL1A antibody is A158. In some embodiments, the anti-TL1A antibodyis A159. In some embodiments, the anti-TL1A antibody is A160. In someembodiments, the anti-TL1A antibody is A161. In some embodiments, theanti-TL1A antibody is A162. In some embodiments, the anti-TL1A antibodyis A163. In some embodiments, the anti-TL1A antibody is A164. In someembodiments, the anti-TL1A antibody is A165. In some embodiments, theanti-TL1A antibody is A166. In some embodiments, the anti-TL1A antibodyis A167. In some embodiments, the anti-TL1A antibody is A168. In someembodiments, the anti-TL1A antibody is A169. In some embodiments, theanti-TL1A antibody is A170. In some embodiments, the anti-TL1A antibodyis A171. In some embodiments, the anti-TL1A antibody is A172. In someembodiments, the anti-TL1A antibody is A173. In some embodiments, theanti-TL1A antibody is A174. In some embodiments, the anti-TL1A antibodyis A175. In some embodiments, the anti-TL1A antibody is A176. In someembodiments, the anti-TL1A antibody is A177.

In some embodiments, the anti-DR3 is A178. In some embodiments, theanti-DR3 is A179. In some embodiments, the anti-DR3 is A180. In someembodiments, the anti-DR3 is A181. In some embodiments, the anti-DR3 isA182. In some embodiments, the anti-DR3 is A183. In some embodiments,the anti-DR3 is A184. In some embodiments, the anti-DR3 is A185. In someembodiments, the anti-DR3 is A186. In some embodiments, the anti-DR3 isA187. In some embodiments, the anti-DR3 is A188. In some embodiments,the anti-DR3 is A189. In some embodiments, the anti-DR3 is A190. In someembodiments, the anti-DR3 is A191. In some embodiments, the anti-DR3 isA192. In some embodiments, the anti-DR3 is A193. In some embodiments,the anti-DR3 is A194. In some embodiments, the anti-DR3 is A195. In someembodiments, the anti-DR3 is A196. In some embodiments, the anti-DR3 isA197. In some embodiments, the anti-DR3 is A198. In some embodiments,the anti-DR3 is A199. In some embodiments, the anti-DR3 is A200. In someembodiments, the anti-DR3 is A201. In some embodiments, the anti-DR3 isA202. In some embodiments, the anti-DR3 is A203. In some embodiments,the anti-DR3 is A204. In some embodiments, the anti-DR3 is A205. In someembodiments, the anti-DR3 is A206. In some embodiments, the anti-DR3 isA207. In some embodiments, the anti-DR3 is A208. In some embodiments,the anti-DR3 is A209. In some embodiments, the anti-DR3 is A210. In someembodiments, the anti-DR3 is A211. In some embodiments, the anti-DR3 isA212. In some embodiments, the anti-DR3 is A213. In some embodiments,the anti-DR3 is A214. In some embodiments, the anti-DR3 is A215. In someembodiments, the anti-DR3 is A216. In some embodiments, the anti-DR3 isA217. In some embodiments, the anti-DR3 is A218. In some embodiments,the anti-DR3 is A219. In some embodiments, the anti-DR3 is A220. In someembodiments, the anti-DR3 is A221. In some embodiments, the anti-DR3 isA222. In some embodiments, the anti-DR3 is A223. In some embodiments,the anti-DR3 is A224. In some embodiments, the anti-DR3 is A225. In someembodiments, the anti-DR3 is A226. In some embodiments, the anti-DR3 isA227. In some embodiments, the anti-DR3 is A228. In some embodiments,the anti-DR3 is A229. In some embodiments, the anti-DR3 is A230. In someembodiments, the anti-DR3 is A231. In some embodiments, the anti-DR3 isA232. In some embodiments, the anti-DR3 is A233. In some embodiments,the anti-DR3 is A234. In some embodiments, the anti-DR3 is A235. In someembodiments, the anti-DR3 is A236. In some embodiments, the anti-DR3 isA237. In some embodiments, the anti-DR3 is A238. In some embodiments,the anti-DR3 is A239. In some embodiments, the anti-DR3 is A240. In someembodiments, the anti-DR3 is A241. In some embodiments, the anti-DR3 isA242.

In some cases, the anti-TL1A antibody binds to at least one or more ofthe same residues of human TL1A as an antibody described herein. Forexample, the anti-TL1A antibody binds to at least one or more of thesame residues of human TL1A as an antibody selected from A100-A177. Insome cases, the anti-TL1A antibody binds to the same epitope of humanTL1A as an antibody selected from A100-A177. In some cases, theanti-TL1A antibody binds to the same region of human TL1A as an antibodyselected from A100-A177.

In some embodiments, the anti-TL1A antibody comprises any one of thefollowing embodiments 1-547 below.

-   -   1. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising: a heavy chain variable region        comprising four heavy chain framework regions (HFR1, HFR2, HFR3,        and HFR4), and three heavy chain complementarity-determining        regions (HCDR1, HCDR2, and HCDR3), the heavy chain variable        region comprising:        -   (a) a HFR1 selected from: (i) a HFR1 comprising SEQ ID NO:            100100, (ii) a HFR1 comprising SEQ ID NO: 100108, and (iii)            a HFR1 comprising an amino acid sequence that differs from a            sequence selected from the group consisting of SEQ ID NOS:            100100 and 100108 by up to five, four, three, or two amino            acids,        -   (b) a HFR2 selected from: (i) a HFR2 comprising SEQ ID NO:            100101, and (ii) a HFR2 comprising an amino acid sequence            that differs from SEQ ID NO: 100101 by up to five, four,            three, or two amino acids,        -   (c) a HFR3 selected from: (i) a HFR3 comprising SEQ ID NO:            100102, (ii) a HFR3 comprising SEQ ID NO: 100109, and (iii)            a HFR3 comprising an amino acid sequence that differs from a            sequence selected from the group consisting of SEQ ID NOS:            100102 and 100109 by up to five, four, three, or two amino            acids,        -   (d) a HFR4 selected from: (i) a HFR4 comprising SEQ ID NO:            100103, and (ii) a HFR4 comprising an amino acid sequence            that differs from SEQ ID NO: 100103 by up to five, four,            three, or two amino acids,        -   (e) a HCDR1 selected from: (i) a HCDR1 comprising SEQ ID NO:            1009, (ii) a HCDR1 comprising SEQ ID NO: 100150, wherein X₁            is selected from D and E, X₂ is selected from I, P and V, X₃            is selected from G, Q, S, and V, X₄ is selected from F and            Y, and X₅ is selected from I and M, (iii) a HCDR1 selected            from SEQ ID NOS: 100200-100295, and (iv) a HCDR1 comprising            an amino acid sequence that differs from a sequence selected            from the group consisting of SEQ ID NOS: 1009, 100150 and            100200-100295 by up to five, four, three, or two amino            acids,        -   (f) a HCDR2 selected from: (i) a HCDR2 comprising SEQ ID NO:            10012, and (ii) a HCDR2 comprising an amino acid sequence            that differs from SEQ ID NO: 10012 by up to five, four,            three, or two amino acids, and        -   (g) a HCDR3 selected from (i) a HCDR3 comprising SEQ ID NO:            10015, (ii) a HCDR3 comprising SEQ ID NO: 100152, wherein X₁            is selected from L and M, and X₂ is selected from E, I, K,            L, M, Q, T, V, W, and Y, (iii) a HCDR3 selected from SEQ ID            NOS: 100296-100314, and (iv) a HCDR3 comprising an amino            acid sequence that differs from a sequence selected from the            group consisting of SEQ ID NOS: 10015, 100152 and            100296-100314 by up to five, four, three, or two amino            acids; and    -   a light chain variable region comprising four light chain        framework regions (LFR1, LFR2, LFR3, and LFR4), and three light        chain complementarity-determining regions (LCDR1, LCDR2, and        LCDR3), the light chain variable region comprising:        -   (a) a LFR1 selected from: (i) a LFR1 comprising SEQ ID NO:            100104, and (ii) a LFR1 comprising an amino acid sequence            that differs from SEQ ID NO: 100104 by up to five, four,            three, or two amino acids,        -   (b) a LFR2 selected from: (i) a LFR2 comprising SEQ ID NO:            100105, and (ii) a LFR2 comprising an amino acid sequence            that differs from SEQ ID NO: 100105 by up to five, four,            three, or two amino acids,        -   (c) a LFR3 selected from: (i) a LFR3 comprising SEQ ID NO:            100106, (ii) a LFR3 comprising SEQ ID NO: 100110, and (iii)            a LFR3 comprising an amino acid sequence that differs from a            sequence selected from the group consisting of SEQ ID NOS:            100106 and 100110 by up to five, four, three, or two amino            acids,        -   (d) a LFR4 selected from: (i) a LFR4 comprising SEQ ID NO:            100107, and (ii) a LFR4 comprising an amino acid sequence            that differs from SEQ ID NO: 100107 by up to five, four,            three, or two amino acids,        -   (e) a LCDR1 selected from: (i) a LCDR1 comprising SEQ ID NO:            10018, and (ii) a LCDR1 comprising an amino acid sequence            that differs from SEQ ID NO: 10018 by up to five, four,            three, or two amino acids,        -   (f) a LCDR2 selected from: (i) a LCDR2 comprising SEQ ID NO:            10021, and (ii) a LCDR2 comprising an amino acid sequence            that differs from SEQ ID NO: 10021 by up to five, four,            three, or two amino acids, and        -   (g) a LCDR3 selected from (i) a LCDR3 comprising SEQ ID NO:            10024, (ii) a LCDR3 comprising SEQ ID NO: 100155, wherein X₁            is selected from Q and N, X₂ is selected from D, E, H, N, Q,            and S, X₃ is selected from A and G, and X₄ is selected from            D, F, K, N, R, S, and T, (iii) a LCDR3 selected from SEQ ID            NOS: 100315-100482, and (iv) a LCDR3 comprising an amino            acid sequence that differs from a sequence selected from the            group consisting of SEQ ID NOS: 10024, 100155, and            100315-100482 by up to five, four, three, or two amino            acids.    -   2. The antibody or antigen-binding fragment of embodiment 1,        provided that the HFR1 comprises SEQ ID NO: 100100.    -   3. The antibody or antigen-binding fragment of embodiment 1,        provided that the HFR1 comprises SEQ ID NO: 100108.    -   4. The antibody or antigen-binding fragment of embodiment 1,        provided that the HFR1 comprises an amino acid sequence that        differs from SEQ ID NO: 100100 by up to five, four, three, or        two amino acids.    -   5. The antibody or antigen-binding fragment of embodiment 1,        provided that the HFR1 comprises an amino acid sequence that        differs from SEQ ID NO: 100108 by up to five, four, three, or        two amino acids.    -   6. The antibody or antigen-binding fragment of any of        embodiments 1-5, provided that the HFR2 comprises SEQ ID NO:        100101.    -   7. The antibody or antigen-binding fragment of any of        embodiments 1-5, provided that the HFR2 comprises an amino acid        sequence that differs from SEQ ID NO: 100101 by up to five,        four, three, or two amino acids.    -   8. The antibody or antigen-binding fragment of any of        embodiments 1-7, provided that the HFR3 comprises SEQ ID NO:        100102.    -   9. The antibody or antigen-binding fragment of any of        embodiments 1-7, provided that the HFR3 comprises SEQ ID NO:        100109.    -   10. The antibody or antigen-binding fragment of any of        embodiments 1-7, provided that the HFR3 comprises an amino acid        sequence that differs from SEQ ID NO: 100102 by up to five,        four, three, or two amino acids.    -   11. The antibody or antigen-binding fragment of any of        embodiments 1-7, provided that the HFR3 comprises an amino acid        sequence that differs from SEQ ID NO: 100109 by up to five,        four, three, or two amino acids.    -   12. The antibody or antigen-binding fragment of any of        embodiments 1-11, provided that the HFR4 comprises SEQ ID NO:        100103.    -   13. The antibody or antigen-binding fragment of any of        embodiments 1-11, provided that the HFR4 comprises an amino acid        sequence that differs from SEQ ID NO: 100103 by up to five,        four, three, or two amino acids.    -   14. The antibody or antigen-binding fragment of any of        embodiments 1-13, provided that the HCDR1 comprises SEQ ID NO:        1009.    -   15. The antibody or antigen-binding fragment of any of        embodiments 1-13, provided that the HCDR1 comprises SEQ ID NO:        100150.    -   16. The antibody or antigen-binding fragment of embodiment 15,        provided that X₁ is E.    -   17. The antibody or antigen-binding fragment of embodiment 15 or        embodiment 16, provided that X₂ is selected from P and V.    -   18. The antibody or antigen-binding fragment of any of        embodiments 15-17, provided that X₃ is selected from G, S, and        V.    -   19. The antibody or antigen-binding fragment of any of        embodiments 15-18, provided that X₄ is F.    -   20. The antibody or antigen-binding fragment of any of        embodiments 15-19, provided that X₅ is I.    -   21. The antibody or antigen-binding fragment of any of        embodiments 1-13, provided that the HCDR1 comprises an amino        acid sequence selected from SEQ ID NOS: 100200-100295.    -   22. The antibody or antigen-binding fragment of any of        embodiments 1-21, provided that the HCDR2 comprises SEQ ID NO:        10012.    -   23. The antibody or antigen-binding fragment of any of        embodiments 1-21, provided that the HCDR2 comprises an amino        acid sequence that differs from SEQ ID NO: 10012 by up to five,        four, three, or two amino acids.    -   24. The antibody or antigen-binding fragment of any of        embodiments 1-23, provided that the HCDR3 comprises SEQ ID NO:        10015.    -   25. The antibody or antigen-binding fragment of any of        embodiments 1-23, provided that the HCDR3 comprises SEQ ID NO:        100152.    -   26. The antibody or antigen-binding fragment of embodiment 25,        provided that X₁ is M.    -   27. The antibody or antigen-binding fragment of embodiment 25 or        embodiment 26, provided that X₂ is selected from E, I, K, L, M,        Q, T, W, and Y.    -   28. The antibody or antigen-binding fragment of any of        embodiments 1-23, provided that the HCDR3 comprises a sequence        selected from SEQ ID NOS: 100296-100314.    -   29. The antibody or antigen-binding fragment of any of        embodiments 1-28, provided that the LFR1 comprises SEQ ID NO:        100104.    -   30. The antibody or antigen-binding fragment of any of        embodiments 1-28, provided that the LFR1 comprises an amino acid        sequence that differs from SEQ ID NO: 100104 by up to five,        four, three, or two amino acids.    -   31. The antibody or antigen-binding fragment of any of        embodiments 1-30, provided that the LFR2 comprises SEQ ID NO:        100105.    -   32. The antibody or antigen-binding fragment of any of        embodiments 1-30, provided that the LFR2 comprises an amino acid        sequence that differs from SEQ ID NO: 100105 by up to five,        four, three, or two amino acids.    -   33. The antibody or antigen-binding fragment of any of        embodiments 1-32, provided that the LFR3 comprises SEQ ID NO:        100106.    -   34. The antibody or antigen-binding fragment of any of        embodiments 1-32, provided that the LFR3 comprises SEQ ID NO:        100110.    -   35. The antibody or antigen-binding fragment of any of        embodiments 1-32, provided that the LFR3 comprises an amino acid        sequence that differs from SEQ ID NO: 100106 by up to five,        four, three, or two amino acids.    -   36. The antibody or antigen-binding fragment of any of        embodiments 1-32, provided that the LFR3 comprises an amino acid        sequence that differs from SEQ ID NO: 100110 by up to five,        four, three, or two amino acids.    -   37. The antibody or antigen-binding fragment of any of        embodiments 1-36, provided that the LFR4 comprises SEQ ID NO:        100107.    -   38. The antibody or antigen-binding fragment of any of        embodiments 1-36, provided that the LFR4 comprises an amino acid        sequence that differs from SEQ ID NO: 100107 by up to five,        four, three, or two amino acids.    -   39. The antibody or antigen-binding fragment of any of        embodiments 1-38, provided that the LCDR1 comprises SEQ ID NO:        10018.    -   40. The antibody or antigen-binding fragment of any of        embodiments 1-38, provided that the LCDR1 comprises an amino        acid sequence that differs from SEQ ID NO: 10018 by up to five,        four, three, or two amino acids.    -   41. The antibody or antigen-binding fragment of any of        embodiments 1-40, provided that the LCDR2 comprises SEQ ID NO:        10021.    -   42. The antibody or antigen-binding fragment of any of        embodiments 1-40, provided that the LCDR2 comprises an amino        acid sequence that differs from SEQ ID NO: 10021 by up to five,        four, three, or two amino acids.    -   43. The antibody or antigen-binding fragment of any of        embodiments 1-42, provided that the LCDR3 comprises SEQ ID NO:        10024.    -   44. The antibody or antigen-binding fragment of any of        embodiments 1-42, provided that the LCDR3 comprises SEQ ID NO:        100155.    -   45. The antibody or antigen-binding fragment of embodiment 44,        provided that X₁ is N. 46. The antibody or antigen-binding        fragment of embodiment 44 or embodiment 45, provided that X₂ is        selected from D, E, H, N, and Q.    -   47. The antibody or antigen-binding fragment of any of        embodiments 44-46, provided that X₃ is A.    -   48. The antibody or antigen-binding fragment of any of        embodiments 44-47, provided that X₄ is selected from D, F, K, R,        S, and T.    -   49. The antibody or antigen-binding fragment of any of        embodiments 1-42, provided that the LCDR3 comprises an amino        acid sequence selected from SEQ ID NOS: 100315-100482.    -   50. The antibody or antigen-binding fragment of embodiment 1,        provided that the HFR1 comprises SEQ ID NO: 100100, the HFR2        comprises SEQ ID NO: 100101, the HFR3 comprises SEQ ID NO:        100102, the HFR4 comprises SEQ ID NO: 100103, the LFRI comprises        SEQ ID NO: 100104, the LFR2 comprises SEQ ID NO: 100105, the        LFR3 comprises SEQ ID NO: 100106, and the LFR4 comprises SEQ ID        NO: 100107.    -   51. The antibody or antigen-binding fragment of embodiment 1,        provided that the HFR1 comprises SEQ ID NO: 100108, the HFR2        comprises SEQ ID NO: 100101, the HFR3 comprises SEQ ID NO:        100109, the HFR4 comprises SEQ ID NO: 100103, the LFRI comprises        SEQ ID NO: 100104, the LFR2 comprises SEQ ID NO: 100105, the        LFR3 comprises SEQ ID NO: 100110, and the LFR4 comprises SEQ ID        NO: 100107.    -   52. The antibody or antigen-binding fragment of embodiment 1,        provided that the HFR1 comprises SEQ ID NO: 100108, the HFR2        comprises SEQ ID NO: 100101, the HFR3 comprises SEQ ID NO:        100109, the HFR4 comprises SEQ ID NO: 100103, the LFRI comprises        SEQ ID NO: 100104, the LFR2 comprises SEQ ID NO: 100105, the        LFR3 comprises SEQ ID NO: 100106, and the LFR4 comprises SEQ ID        NO: 100107.    -   53. The antibody or antigen-binding fragment of any of        embodiments 1 and 50-52, provided that the HCDR1 comprises SEQ        ID NO: 1009, the HCDR2 comprises SEQ ID NO: 10012, the HCDR3        comprises SEQ ID NO: 10015, the LCDR1 comprises SEQ ID NO:        10018, the LCDR2 comprises SEQ ID NO: 10021, and the LCDR3        comprises SEQ ID NO: 10024.    -   54. The antibody or antigen-binding fragment of any of        embodiments 1 and 50-52, provided that the HCDR1 comprises SEQ        ID NO: 100150, the HCDR2 comprises SEQ ID NO: 10012, the HCDR3        comprises SEQ ID NO: 100152, the LCDR1 comprises SEQ ID NO:        10018, the LCDR2 comprises SEQ ID NO: 10021, and the LCDR3        comprises SEQ ID NO: 100155.    -   55. The antibody or antigen-binding fragment of embodiment 1,        provided that the HFR1 comprises SEQ ID NO: 100100, the HFR2        comprises SEQ ID NO: 100101, the HFR3 comprises SEQ ID NO:        100102, the HFR4 comprises SEQ ID NO: 100103, the LFRI comprises        SEQ ID NO: 100104, the LFR2 comprises SEQ ID NO: 100105, the        LFR3 comprises SEQ ID NO: 100106, the LFR4 comprises SEQ ID NO:        100107, the HCDR1 comprises SEQ ID NO: 1009, the HCDR2 comprises        SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO: 10015, the        LCDR1 comprises SEQ ID NO: 10018, the LCDR2 comprises SEQ ID NO:        10021, and the LCDR3 comprises SEQ ID NO: 10024.    -   56. The antibody or antigen-binding fragment of embodiment 1,        provided that the HFR1 comprises SEQ ID NO: 100100, the HFR2        comprises SEQ ID NO: 100101, the HFR3 comprises SEQ ID NO:        100102, the HFR4 comprises SEQ ID NO: 100103, the LFRI comprises        SEQ ID NO: 100104, the LFR2 comprises SEQ ID NO: 100105, the        LFR3 comprises SEQ ID NO: 100106, the LFR4 comprises SEQ ID NO:        100107, the HCDR1 comprises SEQ ID NO: 100150, the HCDR2        comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO:        100152, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2        comprises SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO:        100155.    -   57. The antibody or antigen-binding fragment of embodiment 1,        provided that the HFR1 comprises SEQ ID NO: 100108, the HFR2        comprises SEQ ID NO: 100101, the HFR3 comprises SEQ ID NO:        100109, the HFR4 comprises SEQ ID NO: 100103, the LFRI comprises        SEQ ID NO: 100104, the LFR2 comprises SEQ ID NO: 100105, the        LFR3 comprises SEQ ID NO: 100110, the LFR4 comprises SEQ ID NO:        100107, the HCDR1 comprises SEQ ID NO: 1009, the HCDR2 comprises        SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO: 10015, the        LCDR1 comprises SEQ ID NO: 10018, the LCDR2 comprises SEQ ID NO:        10021, and the LCDR3 comprises SEQ ID NO: 10024.    -   58. The antibody or antigen-binding fragment of embodiment 1,        provided that the HFR1 comprises SEQ ID NO: 100108, the HFR2        comprises SEQ ID NO: 100101, the HFR3 comprises SEQ ID NO:        100109, the HFR4 comprises SEQ ID NO: 100103, the LFRI comprises        SEQ ID NO: 100104, the LFR2 comprises SEQ ID NO: 100105, the        LFR3 comprises SEQ ID NO: 100110, the LFR4 comprises SEQ ID NO:        100107, the HCDR1 comprises SEQ ID NO: 100150, the HCDR2        comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO:        100152, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2        comprises SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO:        100155.    -   59. The antibody or antigen-binding fragment of embodiment 1,        provided that the HFR1 comprises SEQ ID NO: 100108, the HFR2        comprises SEQ ID NO: 100101, the HFR3 comprises SEQ ID NO:        100109, the HFR4 comprises SEQ ID NO: 100103, the LFRI comprises        SEQ ID NO: 100104, the LFR2 comprises SEQ ID NO: 100105, the        LFR3 comprises SEQ ID NO: 100106, the LFR4 comprises SEQ ID NO:        100107, the HCDR1 comprises SEQ ID NO: 1009, the HCDR2 comprises        SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO: 10015, the        LCDR1 comprises SEQ ID NO: 10018, the LCDR2 comprises SEQ ID NO:        10021, and the LCDR3 comprises SEQ ID NO: 10024.    -   60. The antibody or antigen-binding fragment of embodiment 1,        provided that the HFR1 comprises SEQ ID NO: 100108, the HFR2        comprises SEQ ID NO: 100101, the HFR3 comprises SEQ ID NO:        100109, the HFR4 comprises SEQ ID NO: 100103, the LFRI comprises        SEQ ID NO: 100104, the LFR2 comprises SEQ ID NO: 100105, the        LFR3 comprises SEQ ID NO: 100106, the LFR4 comprises SEQ ID NO:        100107, the HCDR1 comprises SEQ ID NO: 100150, the HCDR2        comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO:        100152, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2        comprises SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO:        100155.    -   61. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60, provided that the X₁ of SEQ        ID NO: 100150 is D.    -   62. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60, provided that the X₁ of SEQ        ID NO: 100150 is E.    -   63. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-62, provided that the X₂ of        SEQ ID NO: 100150 is I.    -   64. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-62, provided that the X₂ of        SEQ ID NO: 100150 is P.    -   65. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-62, provided that the X₂ of        SEQ ID NO: 100150 is V.    -   66. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-65, provided that the X₃ of        SEQ ID NO: 100150 is G.    -   67. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-65, provided that the X₃ of        SEQ ID NO: 100150 is Q.    -   68. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-65, provided that the X₃ of        SEQ ID NO: 100150 is S.    -   69. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-65, provided that the X₃ of        SEQ ID NO: 100150 is V.    -   70. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-69, provided that the X₄ of        SEQ ID NO: 100150 is F.    -   71. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-69, provided that the X₄ of        SEQ ID NO: 100150 is Y.    -   72. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-71, provided that the X₅ of        SEQ ID NO: 100150 is I.    -   73. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-71, provided that the X₅ of        SEQ ID NO: 100150 is M.    -   74. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-73, provided that the X₁ of        SEQ ID NO: 100152 is L.    -   75. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-73, provided that the X₁ of        SEQ ID NO: 100152 is M.    -   76. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-75, provided that the X₂ of        SEQ ID NO: 100152 is E.    -   77. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-75, provided that the X₂ of        SEQ ID NO: 100152 is I.    -   78. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-75, provided that the X₂ of        SEQ ID NO: 100152 is K.    -   79. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-75, provided that the X₂ of        SEQ ID NO: 100152 is L.    -   80. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-75, provided that the X₂ of        SEQ ID NO: 100152 is M.    -   81. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-75, provided that the X₂ of        SEQ ID NO: 100152 is Q.    -   82. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-75, provided that the X₂ of        SEQ ID NO: 100152 is T.    -   83. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-75, provided that the X₂ of        SEQ ID NO: 100152 is V.    -   84. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-75, provided that the X₂ of        SEQ ID NO: 100152 is W.    -   85. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-75, provided that the X₂ of        SEQ ID NO: 100152 is Y.    -   86. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-85, provided that the X₁ of        SEQ ID NO: 100155 is Q.    -   87. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-85, provided that the X₁ of        SEQ ID NO: 100155 is N.    -   88. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-87, provided that the X₂ of        SEQ ID NO: 100155 is D.    -   89. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-87, provided that the X₂ of        SEQ ID NO: 100155 is E.    -   90. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-87, provided that the X₂ of        SEQ ID NO: 100155 is H.    -   91. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-87, provided that the X₂ of        SEQ ID NO: 100155 is N.    -   92. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-87, provided that the X₂ of        SEQ ID NO: 100155 is Q.    -   93. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-87, provided that the X₂ of        SEQ ID NO: 100155 is S.    -   94. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-93, provided that the X₃ of        SEQ ID NO: 100155 is A.    -   95. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-93, provided that the X₃ of        SEQ ID NO: 100155 is G.    -   96. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-95, provided that the X₄ of        SEQ ID NO: 100155 is D.    -   97. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-95, provided that the X₄ of        SEQ ID NO: 100155 is F.    -   98. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-95, provided that the X₄ of        SEQ ID NO: 100155 is K.    -   99. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-95, provided that the X₄ of        SEQ ID NO: 100155 is N.    -   100. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-95, provided that the X₄ of        SEQ ID NO: 100155 is R.    -   101. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-95, provided that the X₄ of        SEQ ID NO: 100155 is S.    -   102. The antibody or antigen-binding fragment of any of        embodiments 1, 54, 56, 58, and 60-95, provided that the X₄ of        SEQ ID NO: 100155 is T.    -   103. The antibody or antigen-binding fragment of any of        embodiments 1-102, provided that the antibody or antigen-binding        fragment specifically binds to human TL1A.    -   104. The antibody or antigen-binding fragment of embodiment 103,        provided that the antibody or antigen-binding fragment        specifically binds to human TL1A with a K_(d) of 1×10⁻⁹ M or        less.    -   105. The antibody or antigen-binding fragment of embodiment 104,        provided that the K_(d) is measured using a method selected from        a standard ELISA assay and SPR.    -   106. The antibody or antigen-binding fragment of any of        embodiments 1-105, provided that the antibody or antigen-binding        fragment inhibits binding of DR3 to human TL1A.    -   107. The antibody or antigen-binding fragment of any of        embodiments 1-106, provided that the antibody or antigen-binding        fragment inhibits binding of DcR3 to human TL1A.    -   108. The antibody or antigen-binding fragment of any of        embodiments 1-107, provided that the antibody or antigen-binding        fragment is a humanized antibody, a CDR-grafted antibody, a        chimeric antibody, a Fab, a ScFv, or a combination thereof.    -   109. The antibody or antigen-binding fragment of any of        embodiments 1-108, comprising a human CH1 domain.    -   110. The antibody or antigen-binding fragment of any of        embodiments 1-109, comprising a human CH2 domain.    -   111. The antibody or antigen-binding fragment of embodiment 110,        provided that that CH2 domain comprises at least one mutation        selected from L234A, L235A, and G237A, as numbered using Kabat.    -   112. The antibody or antigen-binding fragment of any of        embodiments 1-111, comprising a human CH3 domain.    -   113. A pharmaceutical composition comprising a therapeutically        effective amount of the antibody or antigen-binding fragment of        any of embodiments 1-112, and a pharmaceutically acceptable        carrier.    -   114. A method of treating an inflammatory disease in a subject        in need thereof, comprising administering to the subject a        therapeutically effective amount of the antibody or        antigen-binding fragment of any of embodiments 1-113.    -   115. The method of embodiment 114, provided that the        inflammatory disease is inflammatory bowel disease.    -   116. The method of embodiment 115, provided that the        inflammatory bowel disease comprises Crohn's disease.    -   117. The method of embodiment 116, provided that the subject has        been determined to be non-responsive to anti-TNF alpha therapy.    -   118. The method of embodiment 116 or embodiment 117, provided        that the subject has been determined to comprise a disease        phenotype comprising non-structuring/non-penetrating,        structuring, structuring and penetrating, or isolated internal        penetrating.    -   119. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising: a heavy chain variable region        comprising four heavy chain framework regions (HFR1, HFR2, HFR3,        and HFR4) comprising SEQ ID NOS: 100100-100103, and three heavy        chain complementarity-determining regions (HCDR1, HCDR2, and        HCDR3) comprising:        -   (a) a HCDR1 selected from: (i) a HCDR1 comprising SEQ ID NO:            1009, (ii) a HCDR1 comprising SEQ ID NO: 100150, wherein X₁            is selected from D and E, X₂ is selected from I, P and V, X₃            is selected from G, Q, S, and V, X₄ is selected from F and            Y, and X₅ is selected from I and M, (iii) a HCDR1 selected            from SEQ ID NOS: 100200-100295, and (iv) a HCDR1 comprising            an amino acid sequence that differs from a sequence selected            from the group consisting of SEQ ID NOS: 1009, 100150 and            100200-100295 by up to five, four, three, or two amino            acids,        -   (b) a HCDR2 selected from: (i) a HCDR2 comprising SEQ ID NO:            10012, and (ii) a HCDR2 comprising an amino acid sequence            that differs from SEQ ID NO: 10012 by up to five, four,            three, or two amino acids, and        -   (c) a HCDR3 selected from (i) a HCDR3 comprising SEQ ID NO:            10015, (ii) a HCDR3 comprising SEQ ID NO: 100152, wherein X₁            is selected from L and M, and X₂ is selected from E, I, K,            L, M, Q, T, V, W, and Y, (iii) a HCDR3 selected from SEQ ID            NOS: 100296-100314, and (iv) a HCDR3 comprising an amino            acid sequence that differs from a sequence selected from the            group consisting of SEQ ID NOS: 10015, 100152 and            100296-100314 by up to five, four, three, or two amino            acids; and    -   a light chain variable region comprising four light chain        framework regions (LFR1, LFR2, LFR3, and LFR4) comprising SEQ ID        NOS: 100104-100107, and three light chain        complementarity-determining regions (LCDR1, LCDR2, and LCDR3)        comprising:        -   (a) a LCDR1 selected from: (i) a LCDR1 comprising SEQ ID NO:            10018, and (ii) a LCDR1 comprising an amino acid sequence            that differs from SEQ ID NO: 10018 by up to five, four,            three, or two amino acids,        -   (b) a LCDR2 selected from: (i) a LCDR2 comprising SEQ ID NO:            10021, and (ii) a LCDR2 comprising an amino acid sequence            that differs from SEQ ID NO: 10021 by up to five, four,            three, or two amino acids, and        -   (c) a LCDR3 selected from (i) a LCDR3 comprising SEQ ID NO:            10024, (ii) a LCDR3 comprising SEQ ID NO: 100155, wherein X₁            is selected from Q and N, X₂ is selected from D, E, H, N, Q,            and S, X₃ is selected from A and G, and X₄ is selected from            D, F, K, N, R, S, and T, (iii) a LCDR3 selected from SEQ ID            NOS: 100315-100482, and (iv) a LCDR3 comprising an amino            acid sequence that differs from a sequence selected from the            group consisting of SEQ ID NOS: 10024, 100155, and            100315-100482 by up to five, four, three, or two amino            acids.    -   120. The antibody or antigen-binding fragment of embodiment 119,        provided that the HCDR1 comprises SEQ ID NO: 1009.    -   121. The antibody or antigen-binding fragment of embodiment 119,        provided that the HCDR1 comprises SEQ ID NO: 100150.    -   122. The antibody or antigen-binding fragment of embodiment 121,        provided that X₁ is E.    -   123. The antibody or antigen-binding fragment of embodiment 121        or embodiment 122, provided that X₂ is selected from P and V.    -   124. The antibody or antigen-binding fragment of any of        embodiments 121-123, provided that X₃ is selected from G, S, and        V.    -   125. The antibody or antigen-binding fragment of any of        embodiments 121-124, provided that X₄ is F.    -   126. The antibody or antigen-binding fragment of any of        embodiments 121-125, provided that X₅ is I.    -   127. The antibody or antigen-binding fragment of embodiment 119,        provided that the HCDR1 comprises an amino acid sequence        selected from SEQ ID NOS: 100200-100295.    -   128. The antibody or antigen-binding fragment of any of        embodiments 119-127, provided that the HCDR2 comprises SEQ ID        NO: 10012.    -   129. The antibody or antigen-binding fragment of any of        embodiments 119-127, provided that the HCDR2 comprises an amino        acid sequence that differs from SEQ ID NO: 10012 by up to five,        four, three, or two amino acids.    -   130. The antibody or antigen-binding fragment of any of        embodiments 119-129, provided that the HCDR3 comprises SEQ ID        NO: 10015.    -   131. The antibody or antigen-binding fragment of any of        embodiments 119-129, provided that the HCDR3 comprises SEQ ID        NO: 100152.    -   132. The antibody or antigen-binding fragment of embodiment 131,        provided that X₁ is M.    -   133. The antibody or antigen-binding fragment of embodiment 131        or embodiment 132, provided that X₂ is selected from E, I, K, L,        M, Q, T, W, and Y.    -   134. The antibody or antigen-binding fragment of any of        embodiments 119-129, provided that the HCDR3 comprises a        sequence selected from SEQ ID NOS: 100296-100314.    -   135. The antibody or antigen-binding fragment of any of        embodiments 119-134, provided that the LCDR1 comprises SEQ ID        NO: 10018.    -   136. The antibody or antigen-binding fragment of any of        embodiments 119-134, provided that the LCDR1 comprises an amino        acid sequence that differs from SEQ ID NO: 10018 by up to five,        four, three, or two amino acids.    -   137. The antibody or antigen-binding fragment of any of        embodiments 119-136, provided that the LCDR2 comprises SEQ ID        NO: 10021.    -   138. The antibody or antigen-binding fragment of any of        embodiments 119-136, provided that the LCDR2 comprises an amino        acid sequence that differs from SEQ ID NO: 10021 by up to five,        four, three, or two amino acids.    -   139. The antibody or antigen-binding fragment of any of        embodiments 119-138, provided that the LCDR3 comprises SEQ ID        NO: 10024.    -   140. The antibody or antigen-binding fragment of any of        embodiments 119-138, provided that the LCDR3 comprises SEQ ID        NO: 100155.    -   141. The antibody or antigen-binding fragment of embodiment 140,        provided that X₁ is N.    -   142. The antibody or antigen-binding fragment of embodiment 140        or embodiment 141, provided that X₂ is selected from D, E, H, N,        and Q.    -   143. The antibody or antigen-binding fragment of any of        embodiments 140-142, provided that X₃ is A.    -   144. The antibody or antigen-binding fragment of any of        embodiments 140-143, provided that X₄ is selected from D, F, K,        R, S, and T.    -   145. The antibody or antigen-binding fragment of any of        embodiments 119-138, provided that the LCDR3 comprises an amino        acid sequence selected from SEQ ID NOS: 100315-100482.    -   146. The antibody or antigen-binding fragment of embodiment 119,        provided that the HCDR1 comprises SEQ ID NO: 1009, the HCDR2        comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO:        10015, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2 comprises        SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO: 10024.    -   147. The antibody or antigen-binding fragment of embodiment 119,        provided that the HCDR1 comprises SEQ ID NO: 100150, the HCDR2        comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO:        100152, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2        comprises SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO:        100155.    -   148. The antibody or antigen-binding fragment of embodiment 119        or embodiment 147, provided that the X₁ of SEQ ID NO: 100150 is        D.    -   149. The antibody or antigen-binding fragment of embodiment 119        or embodiment 147 provided that the X₁ of SEQ ID NO: 100150 is        E.    -   150. The antibody or antigen-binding fragment of any of        embodiments 119, 147-149, provided that the X₂ of SEQ ID NO:        100150 is I.    -   151. The antibody or antigen-binding fragment of any of        embodiments 119, 147-149, provided that the X₂ of SEQ ID NO:        100150 is P.    -   152. The antibody or antigen-binding fragment of any of        embodiments 119, 147-149, provided that the X₂ of SEQ ID NO:        100150 is V.    -   153. The antibody or antigen-binding fragment of any of        embodiments 119, 147-152, provided that the X₃ of SEQ ID NO:        100150 is G.    -   154. The antibody or antigen-binding fragment of any of        embodiments 119, 147-152, provided that the X₃ of SEQ ID NO:        100150 is Q.    -   155. The antibody or antigen-binding fragment of any of        embodiments 119, 147-152, provided that the X₃ of SEQ ID NO:        100150 is S.    -   156. The antibody or antigen-binding fragment of any of        embodiments 119, 147-152, provided that the X₃ of SEQ ID NO:        100150 is V.    -   157. The antibody or antigen-binding fragment of any of        embodiments 119, 147-156, provided that the X₄ of SEQ ID NO:        100150 is F.    -   158. The antibody or antigen-binding fragment of any of        embodiments 119, 147-156, provided that the X₄ of SEQ ID NO:        100150 is Y.    -   159. The antibody or antigen-binding fragment of any of        embodiments 119, 147-158, provided that the X₅ of SEQ ID NO:        100150 is I.    -   160. The antibody or antigen-binding fragment of any of        embodiments 119, 147-158, provided that the X₅ of SEQ ID NO:        100150 is M.    -   161. The antibody or antigen-binding fragment of any of        embodiments 119, 147-160, provided that the X₁ of SEQ ID NO:        100152 is L.    -   162. The antibody or antigen-binding fragment of any of        embodiments 119, 147-160, provided that the X₁ of SEQ ID NO:        100152 is M.    -   163. The antibody or antigen-binding fragment of any of        embodiments 119, 147-162, provided that the X₂ of SEQ ID NO:        100152 is E.    -   164. The antibody or antigen-binding fragment of any of        embodiments 119, 147-162, provided that the X₂ of SEQ ID NO:        100152 is I.    -   165. The antibody or antigen-binding fragment of any of        embodiments 119, 147-162, provided that the X₂ of SEQ ID NO:        100152 is K.    -   166. The antibody or antigen-binding fragment of any of        embodiments 119, 147-162, provided that the X₂ of SEQ ID NO:        100152 is L.    -   167. The antibody or antigen-binding fragment of any of        embodiments 119, 147-162, provided that the X₂ of SEQ ID NO:        100152 is M.    -   168. The antibody or antigen-binding fragment of any of        embodiments 119, 147-162, provided that the X₂ of SEQ ID NO:        100152 is Q.    -   169. The antibody or antigen-binding fragment of any of        embodiments 119, 147-162, provided that the X₂ of SEQ ID NO:        100152 is T.    -   170. The antibody or antigen-binding fragment of any of        embodiments 119, 147-162, provided that the X₂ of SEQ ID NO:        100152 is V.    -   171. The antibody or antigen-binding fragment of any of        embodiments 119, 147-162, provided that the X₂ of SEQ ID NO:        100152 is W.    -   172. The antibody or antigen-binding fragment of any of        embodiments 119, 147-162, provided that the X₂ of SEQ ID NO:        100152 is Y.    -   173. The antibody or antigen-binding fragment of any of        embodiments 119, 147-172, provided that the X₁ of SEQ ID NO:        100155 is Q.    -   174. The antibody or antigen-binding fragment of any of        embodiments 119, 147-172, provided that the X₁ of SEQ ID NO:        100155 is N.    -   175. The antibody or antigen-binding fragment of any of        embodiments 119, 147-174, provided that the X₂ of SEQ ID NO:        100155 is D.    -   176. The antibody or antigen-binding fragment of any of        embodiments 119, 147-174, provided that the X₂ of SEQ ID NO:        100155 is E.    -   177. The antibody or antigen-binding fragment of any of        embodiments 119, 147-174, provided that the X₂ of SEQ ID NO:        100155 is H.    -   178. The antibody or antigen-binding fragment of any of        embodiments 119, 147-174, provided that the X₂ of SEQ ID NO:        100155 is N.    -   179. The antibody or antigen-binding fragment of any of        embodiments 119, 147-174, provided that the X₂ of SEQ ID NO:        100155 is Q.    -   180. The antibody or antigen-binding fragment of any of        embodiments 119, 147-174, provided that the X₂ of SEQ ID NO:        100155 is S.    -   181. The antibody or antigen-binding fragment of any of        embodiments 119, 147-180, provided that the X₃ of SEQ ID NO:        100155 is A.    -   182. The antibody or antigen-binding fragment of any of        embodiments 119, 147-180, provided that the X₃ of SEQ ID NO:        100155 is G.    -   183. The antibody or antigen-binding fragment of any of        embodiments 119, 147-182, provided that the X₄ of SEQ ID NO:        100155 is D.    -   184. The antibody or antigen-binding fragment of any of        embodiments 119, 147-182, provided that the X₄ of SEQ ID NO:        100155 is F.    -   185. The antibody or antigen-binding fragment of any of        embodiments 119, 147-182, provided that the X₄ of SEQ ID NO:        100155 is K.    -   186. The antibody or antigen-binding fragment of any of        embodiments 119, 147-182, provided that the X₄ of SEQ ID NO:        100155 is N.    -   187. The antibody or antigen-binding fragment of any of        embodiments 119, 147-182, provided that the X₄ of SEQ ID NO:        100155 is R.    -   188. The antibody or antigen-binding fragment of any of        embodiments 119, 147-182, provided that the X₄ of SEQ ID NO:        100155 is S.    -   189. The antibody or antigen-binding fragment of any of        embodiments 119, 147-182, provided that the X₄ of SEQ ID NO:        100155 is T.    -   190. The antibody or antigen-binding fragment of any of        embodiments 119-189, provided that the antibody or        antigen-binding fragment specifically binds to human TL1A.    -   191. The antibody or antigen-binding fragment of embodiment 190,        provided that the antibody or antigen-binding fragment        specifically binds to human TL1A with a K_(d) of 1×10⁻⁹ M or        less.    -   192. The antibody or antigen-binding fragment of embodiment 191,        provided that the K_(d) is measured using a method selected from        a standard ELISA assay and SPR.    -   193. The antibody or antigen-binding fragment of any of        embodiments 119-192, provided that the antibody or        antigen-binding fragment inhibits binding of DR3 to human TL1A.    -   194. The antibody or antigen-binding fragment of any of        embodiments 119-193, provided that the antibody or        antigen-binding fragment inhibits binding of DcR3 to human TL1A.    -   195. The antibody or antigen-binding fragment of any of        embodiments 119-194, provided that the antibody or        antigen-binding fragment is a humanized antibody, a CDR-grafted        antibody, a chimeric antibody, a Fab, a ScFv, or a combination        thereof.    -   196. The antibody or antigen-binding fragment of any of        embodiments 119-195, comprising a human CH1 domain.    -   197. The antibody or antigen-binding fragment of any of        embodiments 119-196, comprising a human CH2 domain.    -   198. The antibody or antigen-binding fragment of embodiment 197,        provided that that CH2 domain comprises at least one mutation        selected from L234A, L235A, and G237A, as numbered using Kabat.    -   199. The antibody or antigen-binding fragment of any of        embodiments 119-198, comprising a human CH3 domain.    -   200. A pharmaceutical composition comprising a therapeutically        effective amount of the antibody or antigen-binding fragment of        any of embodiments 119-199, and a pharmaceutically acceptable        carrier.    -   201. A method of treating an inflammatory disease in a subject        in need thereof, comprising administering to the subject a        therapeutically effective amount of the antibody or        antigen-binding fragment of any of embodiments 119-199.    -   202. The method of embodiment 201, provided that the        inflammatory disease is inflammatory bowel disease.    -   203. The method of embodiment 202, provided that the        inflammatory bowel disease comprises Crohn's disease.    -   204. The method of embodiment 203, provided that the subject has        been determined to be non-responsive to anti-TNF alpha therapy.    -   205. The method of embodiment 203 or embodiment 204, provided        that the subject has been determined to comprise a disease        phenotype comprising non-structuring/non-penetrating,        structuring, structuring and penetrating, or isolated internal        penetrating.    -   206. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising: a heavy chain variable region        comprising four heavy chain framework regions (HFR1, HFR2, HFR3,        and HFR4) comprising SEQ ID NOS: 100108, 100101, 100109, and        100103, respectively, and three heavy chain        complementarity-determining regions (HCDR1, HCDR2, and HCDR3)        comprising:        -   (a) a HCDR1 selected from: (i) a HCDR1 comprising SEQ ID NO:            1009, (ii) a HCDR1 comprising SEQ ID NO: 100150, wherein X₁            is selected from D and E, X₂ is selected from I, P and V, X₃            is selected from G, Q, S, and V, X₄ is selected from F and            Y, and X₅ is selected from I and M, (iii) a HCDR1 selected            from SEQ ID NOS: 100200-100295, and (iv) a HCDR1 comprising            an amino acid sequence that differs from a sequence selected            from the group consisting of SEQ ID NOS: 1009, 100150 and            100200-100295 by up to five, four, three, or two amino            acids,        -   (b) a HCDR2 selected from: (i) a HCDR2 comprising SEQ ID NO:            10012, and (ii) a HCDR2 comprising an amino acid sequence            that differs from SEQ ID NO: 10012 by up to five, four,            three, or two amino acids, and        -   (c) a HCDR3 selected from (i) a HCDR3 comprising SEQ ID NO:            10015, (ii) a HCDR3 comprising SEQ ID NO: 100152, wherein X₁            is selected from L and M, and X₂ is selected from E, I, K,            L, M, Q, T, V, W, and Y, (iii) a HCDR3 selected from SEQ ID            NOS: 100296-100314, and (iv) a HCDR3 comprising an amino            acid sequence that differs from a sequence selected from the            group consisting of SEQ ID NOS: 10015, 100152 and            100296-100314 by up to five, four, three, or two amino            acids; and    -   a light chain variable region comprising four light chain        framework regions (LFR1, LFR2, LFR3, and LFR4) comprising SEQ ID        NOS: 100104, 100105, 100110, and 100107, respectively, and three        light chain complementarity-determining regions (LCDR1, LCDR2,        and LCDR3) comprising:        -   (a) a LCDR1 selected from: (i) a LCDR1 comprising SEQ ID NO:            10018, and (ii) a LCDR1 comprising an amino acid sequence            that differs from SEQ ID NO: 10018 by up to five, four,            three, or two amino acids,        -   (b) a LCDR2 selected from: (i) a LCDR2 comprising SEQ ID NO:            10021, and (ii) a LCDR2 comprising an amino acid sequence            that differs from SEQ ID NO: 10021 by up to five, four,            three, or two amino acids, and        -   (c) a LCDR3 selected from (i) a LCDR3 comprising SEQ ID NO:            10024, (ii) a LCDR3 comprising SEQ ID NO: 100155, wherein X₁            is selected from Q and N, X₂ is selected from D, E, H, N, Q,            and S, X₃ is selected from A and G, and X₄ is selected from            D, F, K, N, R, S, and T, (iii) a LCDR3 selected from SEQ ID            NOS: 100315-100482, and (iv) a LCDR3 comprising an amino            acid sequence that differs from a sequence selected from the            group consisting of SEQ ID NOS: 10024, 100155, and            100315-100482 by up to five, four, three, or two amino            acids.    -   207. The antibody or antigen-binding fragment of embodiment 206,        provided that the HCDR1 comprises SEQ ID NO: 1009.    -   208. The antibody or antigen-binding fragment of embodiment 206,        provided that the HCDR1 comprises SEQ ID NO: 100150.    -   209. The antibody or antigen-binding fragment of embodiment 208,        provided that X₁ is E.    -   210. The antibody or antigen-binding fragment of embodiment 208        or embodiment 209, provided that X₂ is selected from P and V.    -   211. The antibody or antigen-binding fragment of any of        embodiments 208-210, provided that X₃ is selected from G, S, and        V.    -   212. The antibody or antigen-binding fragment of any of        embodiments 208-211, provided that X₄ is F.    -   213. The antibody or antigen-binding fragment of any of        embodiments 208-212, provided that X₅ is I.    -   214. The antibody or antigen-binding fragment of embodiment 206,        provided that the HCDR1 comprises an amino acid sequence        selected from SEQ ID NOS: 100200-100295.    -   215. The antibody or antigen-binding fragment of any of        embodiments 206-214, provided that the HCDR2 comprises SEQ ID        NO: 10012.    -   216. The antibody or antigen-binding fragment of any of        embodiments 206-214, provided that the HCDR2 comprises an amino        acid sequence that differs from SEQ ID NO: 10012 by up to five,        four, three, or two amino acids.    -   217. The antibody or antigen-binding fragment of any of        embodiments 206-216, provided that the HCDR3 comprises SEQ ID        NO: 10015.    -   218. The antibody or antigen-binding fragment of any of        embodiments 206-216, provided that the HCDR3 comprises SEQ ID        NO: 100152.    -   219. The antibody or antigen-binding fragment of embodiment 218,        provided that X₁ is M.    -   220. The antibody or antigen-binding fragment of embodiment 218        or embodiment 219, provided that X₂ is selected from E, I, K, L,        M, Q, T, W, and Y.    -   221. The antibody or antigen-binding fragment of any of        embodiments 206-220, provided that the HCDR3 comprises a        sequence selected from SEQ ID NOS: 100296-100314.    -   222. The antibody or antigen-binding fragment of any of        embodiments 206-221, provided that the LCDR1 comprises SEQ ID        NO: 10018.    -   223. The antibody or antigen-binding fragment of any of        embodiments 206-221, provided that the LCDR1 comprises an amino        acid sequence that differs from SEQ ID NO: 10018 by up to five,        four, three, or two amino acids.    -   224. The antibody or antigen-binding fragment of any of        embodiments 206-223, provided that the LCDR2 comprises SEQ ID        NO: 10021.    -   225. The antibody or antigen-binding fragment of any of        embodiments 206-223, provided that the LCDR2 comprises an amino        acid sequence that differs from SEQ ID NO: 10021 by up to five,        four, three, or two amino acids.    -   226. The antibody or antigen-binding fragment of any of        embodiments 206-225, provided that the LCDR3 comprises SEQ ID        NO: 10024.    -   227. The antibody or antigen-binding fragment of any of        embodiments 206-225, provided that the LCDR3 comprises SEQ ID        NO: 100155.    -   228. The antibody or antigen-binding fragment of embodiment 227,        provided that X₁ is N.    -   229. The antibody or antigen-binding fragment of embodiment 227        or embodiment 228, provided that X₂ is selected from D, E, H, N,        and Q.    -   230. The antibody or antigen-binding fragment of any of        embodiments 227-229, provided that X₃ is A.    -   231. The antibody or antigen-binding fragment of any of        embodiments 227-230, provided that X₄ is selected from D, F, K,        R, S, and T.    -   232. The antibody or antigen-binding fragment of any of        embodiments 227-231, provided that the LCDR3 comprises an amino        acid sequence selected from SEQ ID NOS: 100315-100482.    -   233. The antibody or antigen-binding fragment of embodiment 206,        provided that the HCDR1 comprises SEQ ID NO: 1009, the HCDR2        comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO:        10015, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2 comprises        SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO: 10024.    -   234. The antibody or antigen-binding fragment of embodiment 206,        provided that the HCDR1 comprises SEQ ID NO: 100150, the HCDR2        comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO:        100152, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2        comprises SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO:        100155.    -   235. The antibody or antigen-binding fragment of embodiment 206        or embodiment 234, provided that the X₁ of SEQ ID NO: 100150 is        D.    -   236. The antibody or antigen-binding fragment of embodiment 206        or embodiment 234 provided that the X₁ of SEQ ID NO: 100150 is        E.    -   237. The antibody or antigen-binding fragment of any of        embodiments 206, 234-236, provided that the X₂ of SEQ ID NO:        100150 is I.    -   238. The antibody or antigen-binding fragment of any of        embodiments 206, 234-236, provided that the X₂ of SEQ ID NO:        100150 is P.    -   239. The antibody or antigen-binding fragment of any of        embodiments 206, 234-236, provided that the X₂ of SEQ ID NO:        100150 is V.    -   240. The antibody or antigen-binding fragment of any of        embodiments 206, 234-239, provided that the X₃ of SEQ ID NO:        100150 is G.    -   241. The antibody or antigen-binding fragment of any of        embodiments 206, 234-239, provided that the X₃ of SEQ ID NO:        100150 is Q.    -   242. The antibody or antigen-binding fragment of any of        embodiments 206, 234-239, provided that the X₃ of SEQ ID NO:        100150 is S.    -   243. The antibody or antigen-binding fragment of any of        embodiments 206, 234-239, provided that the X₃ of SEQ ID NO:        100150 is V.    -   244. The antibody or antigen-binding fragment of any of        embodiments 206, 234-243, provided that the X₄ of SEQ ID NO:        100150 is F.    -   245. The antibody or antigen-binding fragment of any of        embodiments 206, 234-243, provided that the X₄ of SEQ ID NO:        100150 is Y.    -   246. The antibody or antigen-binding fragment of any of        embodiments 206, 234-245, provided that the X₅ of SEQ ID NO:        100150 is I.    -   247. The antibody or antigen-binding fragment of any of        embodiments 206, 234-245, provided that the X₅ of SEQ ID NO:        100150 is M.    -   248. The antibody or antigen-binding fragment of any of        embodiments 206, 234-247, provided that the X₁ of SEQ ID NO:        100152 is L.    -   249. The antibody or antigen-binding fragment of any of        embodiments 206, 234-247, provided that the X₁ of SEQ ID NO:        100152 is M.    -   250. The antibody or antigen-binding fragment of any of        embodiments 206, 234-249, provided that the X₂ of SEQ ID NO:        100152 is E.    -   251. The antibody or antigen-binding fragment of any of        embodiments 206, 234-249, provided that the X₂ of SEQ ID NO:        100152 is I.    -   252. The antibody or antigen-binding fragment of any of        embodiments 206, 234-249, provided that the X₂ of SEQ ID NO:        100152 is K.    -   253. The antibody or antigen-binding fragment of any of        embodiments 206, 234-249, provided that the X₂ of SEQ ID NO:        100152 is L.    -   254. The antibody or antigen-binding fragment of any of        embodiments 206, 234-249, provided that the X₂ of SEQ ID NO:        100152 is M.    -   255. The antibody or antigen-binding fragment of any of        embodiments 206, 234-249, provided that the X₂ of SEQ ID NO:        100152 is Q.    -   256. The antibody or antigen-binding fragment of any of        embodiments 206, 234-249, provided that the X₂ of SEQ ID NO:        100152 is T.    -   257. The antibody or antigen-binding fragment of any of        embodiments 206, 234-249, provided that the X₂ of SEQ ID NO:        100152 is V.    -   258. The antibody or antigen-binding fragment of any of        embodiments 206, 234-249, provided that the X₂ of SEQ ID NO:        100152 is W.    -   259. The antibody or antigen-binding fragment of any of        embodiments 206, 234-249, provided that the X₂ of SEQ ID NO:        100152 is Y.    -   260. The antibody or antigen-binding fragment of any of        embodiments 206, 234-259, provided that the X₁ of SEQ ID NO:        100155 is Q.    -   261. The antibody or antigen-binding fragment of any of        embodiments 206, 234-259, provided that the X₁ of SEQ ID NO:        100155 is N.    -   262. The antibody or antigen-binding fragment of any of        embodiments 206, 234-261, provided that the X₂ of SEQ ID NO:        100155 is D.    -   263. The antibody or antigen-binding fragment of any of        embodiments 206, 234-261, provided that the X₂ of SEQ ID NO:        100155 is E.    -   264. The antibody or antigen-binding fragment of any of        embodiments 206, 234-261, provided that the X₂ of SEQ ID NO:        100155 is H.    -   265. The antibody or antigen-binding fragment of any of        embodiments 206, 234-261, provided that the X₂ of SEQ ID NO:        100155 is N.    -   266. The antibody or antigen-binding fragment of any of        embodiments 206, 234-261, provided that the X₂ of SEQ ID NO:        100155 is Q.    -   267. The antibody or antigen-binding fragment of any of        embodiments 206, 234-261, provided that the X₂ of SEQ ID NO:        100155 is S.    -   268. The antibody or antigen-binding fragment of any of        embodiments 206, 234-267, provided that the X₃ of SEQ ID NO:        100155 is A.    -   269. The antibody or antigen-binding fragment of any of        embodiments 206, 234-267, provided that the X₃ of SEQ ID NO:        100155 is G.    -   270. The antibody or antigen-binding fragment of any of        embodiments 206, 234-269, provided that the X₄ of SEQ ID NO:        100155 is D.    -   271. The antibody or antigen-binding fragment of any of        embodiments 206, 234-269, provided that the X₄ of SEQ ID NO:        100155 is F.    -   272. The antibody or antigen-binding fragment of any of        embodiments 206, 234-269, provided that the X₄ of SEQ ID NO:        100155 is K.    -   273. The antibody or antigen-binding fragment of any of        embodiments 206, 234-269, provided that the X₄ of SEQ ID NO:        100155 is N.    -   274. The antibody or antigen-binding fragment of any of        embodiments 206, 234-269, provided that the X₄ of SEQ ID NO:        100155 is R.    -   275. The antibody or antigen-binding fragment of any of        embodiments 206, 234-269, provided that the X₄ of SEQ ID NO:        100155 is S.    -   276. The antibody or antigen-binding fragment of any of        embodiments 206, 234-269, provided that the X₄ of SEQ ID NO:        100155 is T.    -   277. The antibody or antigen-binding fragment of any of        embodiments 206-276, provided that the antibody or        antigen-binding fragment specifically binds to human TL1A.    -   278. The antibody or antigen-binding fragment of embodiment 277,        provided that the antibody or antigen-binding fragment        specifically binds to human TL1A with a K_(d) of 1×10⁻⁹ M or        less.    -   279. The antibody or antigen-binding fragment of embodiment 278,        provided that the K_(d) is measured using a method selected from        a standard ELISA assay and SPR.    -   280. The antibody or antigen-binding fragment of any of        embodiments 206-279, provided that the antibody or        antigen-binding fragment inhibits binding of DR3 to human TL1A.    -   281. The antibody or antigen-binding fragment of any of        embodiments 206-280, provided that the antibody or        antigen-binding fragment inhibits binding of DcR3 to human TL1A.    -   282. The antibody or antigen-binding fragment of any of        embodiments 206-281, provided that the antibody or        antigen-binding fragment is a humanized antibody, a CDR-grafted        antibody, a chimeric antibody, a Fab, a ScFv, or a combination        thereof.    -   283. The antibody or antigen-binding fragment of any of        embodiments 206-282, comprising a human CH1 domain.    -   284. The antibody or antigen-binding fragment of any of        embodiments 206-283, comprising a human CH2 domain.    -   285. The antibody or antigen-binding fragment of embodiment 284,        provided that that CH2 domain comprises at least one mutation        selected from L234A, L235A, and G237A, as numbered using Kabat.    -   286. The antibody or antigen-binding fragment of any of        embodiments 206-285, comprising a human CH3 domain.    -   287. A pharmaceutical composition comprising a therapeutically        effective amount of the antibody or antigen-binding fragment of        any of embodiments 206-286, and a pharmaceutically acceptable        carrier.    -   288. A method of treating an inflammatory disease in a subject        in need thereof, comprising administering to the subject a        therapeutically effective amount of the antibody or        antigen-binding fragment of any of embodiments 206-287.    -   289. The method of embodiment 288, provided that the        inflammatory disease is inflammatory bowel disease.    -   290. The method of embodiment 289, provided that the        inflammatory bowel disease comprises Crohn's disease.    -   291. The method of embodiment 290, provided that the subject has        been determined to be non-responsive to anti-TNF alpha therapy.    -   292. The method of embodiment 290 or embodiment 291, provided        that the subject has been determined to comprise a disease        phenotype comprising non-structuring/non-penetrating,        structuring, structuring and penetrating, or isolated internal        penetrating.    -   293. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising: a heavy chain variable region        comprising four heavy chain framework regions (HFR1, HFR2, HFR3,        and HFR4) comprising SEQ ID NOS: 100108, 100101, 100109, and        100103, respectively, and three heavy chain        complementarity-determining regions (HCDR1, HCDR2, and HCDR3)        comprising:        -   (a) a HCDR1 selected from: (i) a HCDR1 comprising SEQ ID NO:            1009, (ii) a HCDR1 comprising SEQ ID NO: 100150, wherein X₁            is selected from D and E, X₂ is selected from I, P and V, X₃            is selected from G, Q, S, and V, X₄ is selected from F and            Y, and X₅ is selected from I and M, (iii) a HCDR1 selected            from SEQ ID NOS: 100200-100295, and (iv) a HCDR1 comprising            an amino acid sequence that differs from a sequence selected            from the group consisting of SEQ ID NOS: 1009, 100150 and            100200-100295 by up to five, four, three, or two amino            acids,        -   (b) a HCDR2 selected from: (i) a HCDR2 comprising SEQ ID NO:            10012, and (ii) a HCDR2 comprising an amino acid sequence            that differs from SEQ ID NO: 10012 by up to five, four,            three, or two amino acids, and        -   (c) a HCDR3 selected from (i) a HCDR3 comprising SEQ ID NO:            10015, (ii) a HCDR3 comprising SEQ ID NO: 100152, wherein X₁            is selected from L and M, and X₂ is selected from E, I, K,            L, M, Q, T, V, W, and Y, (iii) a HCDR3 selected from SEQ ID            NOS: 100296-100314, and (iv) a HCDR3 comprising an amino            acid sequence that differs from a sequence selected from the            group consisting of SEQ ID NOS: 10015, 100152 and            100296-100314 by up to five, four, three, or two amino            acids; and    -   a light chain variable region comprising four light chain        framework regions (LFR1, LFR2, LFR3, and LFR4) comprising SEQ ID        NOS: 100104-100107, and three light chain        complementarity-determining regions (LCDR1, LCDR2, and LCDR3)        comprising:        -   (a) a LCDR1 selected from: (i) a LCDR1 comprising SEQ ID NO:            10018, and (ii) a LCDR1 comprising an amino acid sequence            that differs from SEQ ID NO: 10018 by up to five, four,            three, or two amino acids,        -   (b) a LCDR2 selected from: (i) a LCDR2 comprising SEQ ID NO:            10021, and (ii) a LCDR2 comprising an amino acid sequence            that differs from SEQ ID NO: 10021 by up to five, four,            three, or two amino acids, and        -   (c) a LCDR3 selected from (i) a LCDR3 comprising SEQ ID NO:            10024, (ii) a LCDR3 comprising SEQ ID NO: 100155, wherein X₁            is selected from Q and N, X₂ is selected from D, E, H, N, Q,            and S, X₃ is selected from A and G, and X₄ is selected from            D, F, K, N, R, S, and T, (iii) a LCDR3 selected from SEQ ID            NOS: 100315-100482, and (iv) a LCDR3 comprising an amino            acid sequence that differs from a sequence selected from the            group consisting of SEQ ID NOS: 10024, 100155, and            100315-100482 by up to five, four, three, or two amino            acids.    -   294. The antibody or antigen-binding fragment of embodiment 293,        provided that the HCDR1 comprises SEQ ID NO: 1009.    -   295. The antibody or antigen-binding fragment of embodiment 293,        provided that the HCDR1 comprises SEQ ID NO: 100150.    -   296. The antibody or antigen-binding fragment of embodiment 295,        provided that X₁ is E.    -   297. The antibody or antigen-binding fragment of embodiment 295        or embodiment 296, provided that X₂ is selected from P and V.    -   298. The antibody or antigen-binding fragment of any of        embodiments 295-297, provided that X₃ is selected from G, S, and        V.    -   299. The antibody or antigen-binding fragment of any of        embodiments 295-298, provided that X₄ is F.    -   300. The antibody or antigen-binding fragment of any of        embodiments 295-299, provided that X₅ is I.    -   301. The antibody or antigen-binding fragment of embodiment 293,        provided that the HCDR1 comprises an amino acid sequence        selected from SEQ ID NOS: 100200-100295.    -   302. The antibody or antigen-binding fragment of any of        embodiments 293-301, provided that the HCDR2 comprises SEQ ID        NO: 10012.    -   303. The antibody or antigen-binding fragment of any of        embodiments 293-301 provided that the HCDR2 comprises an amino        acid sequence that differs from SEQ ID NO: 10012 by up to five,        four, three, or two amino acids.    -   304. The antibody or antigen-binding fragment of any of        embodiments 293-303, provided that the HCDR3 comprises SEQ ID        NO: 10015.    -   305. The antibody or antigen-binding fragment of any of        embodiments 293-303, provided that the HCDR3 comprises SEQ ID        NO: 100152.    -   306. The antibody or antigen-binding fragment of embodiment 305,        provided that X₁ is M.    -   307. The antibody or antigen-binding fragment of embodiment 305        or embodiment 306, provided that X₂ is selected from E, I, K, L,        M, Q, T, W, and Y.    -   308. The antibody or antigen-binding fragment of any of        embodiments 293-303, provided that the HCDR3 comprises a        sequence selected from SEQ ID NOS: 100296-100314.    -   309. The antibody or antigen-binding fragment of any of        embodiments 293-308, provided that the LCDR1 comprises SEQ ID        NO: 10018.    -   310. The antibody or antigen-binding fragment of any of        embodiments 293-308, provided that the LCDR1 comprises an amino        acid sequence that differs from SEQ ID NO: 10018 by up to five,        four, three, or two amino acids.    -   311. The antibody or antigen-binding fragment of any of        embodiments 293-310, provided that the LCDR2 comprises SEQ ID        NO: 10021.    -   312. The antibody or antigen-binding fragment of any of        embodiments 293-310, provided that the LCDR2 comprises an amino        acid sequence that differs from SEQ ID NO: 10021 by up to five,        four, three, or two amino acids.    -   313. The antibody or antigen-binding fragment of any of        embodiments 293-312, provided that the LCDR3 comprises SEQ ID        NO: 10024.    -   314. The antibody or antigen-binding fragment of any of        embodiments 293-312, provided that the LCDR3 comprises SEQ ID        NO: 100155.    -   315. The antibody or antigen-binding fragment of embodiment 314,        provided that X₁ is N.    -   316. The antibody or antigen-binding fragment of embodiment 314        or embodiment 315, provided that X₂ is selected from D, E, H, N,        and Q.    -   317. The antibody or antigen-binding fragment of any of        embodiments 314-316, provided that X₃ is A.    -   318. The antibody or antigen-binding fragment of any of        embodiments 314-317, provided that X4 is selected from D, F, K,        R, S, and T.    -   319. The antibody or antigen-binding fragment of any of        embodiments 314-312, provided that the LCDR3 comprises an amino        acid sequence selected from SEQ ID NOS: 100315-100482.    -   320. The antibody or antigen-binding fragment of embodiment 293,        provided that the HCDR1 comprises SEQ ID NO: 1009, the HCDR2        comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO:        10015, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2 comprises        SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO: 10024.    -   321. The antibody or antigen-binding fragment of embodiment 293,        provided that the HCDR1 comprises SEQ ID NO: 100150, the HCDR2        comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO:        100152, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2        comprises SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO:        100155.    -   322. The antibody or antigen-binding fragment of embodiment 293        or embodiment 321, provided that the X₁ of SEQ ID NO: 100150 is        D.    -   323. The antibody or antigen-binding fragment of embodiment 293        or embodiment 321 provided that the X₁ of SEQ ID NO: 100150 is        E.    -   324. The antibody or antigen-binding fragment of any of        embodiments 293, 321-323, provided that the X₂ of SEQ ID NO:        100150 is I.    -   325. The antibody or antigen-binding fragment of any of        embodiments 293, 321-323, provided that the X₂ of SEQ ID NO:        100150 is P.    -   326. The antibody or antigen-binding fragment of any of        embodiments 293, 321-323, provided that the X₂ of SEQ ID NO:        100150 is V.    -   327. The antibody or antigen-binding fragment of any of        embodiments 293, 321-326, provided that the X₃ of SEQ ID NO:        100150 is G.    -   328. The antibody or antigen-binding fragment of any of        embodiments 293, 321-326, provided that the X₃ of SEQ ID NO:        100150 is Q.    -   329. The antibody or antigen-binding fragment of any of        embodiments 293, 321-326, provided that the X₃ of SEQ ID NO:        100150 is S.    -   330. The antibody or antigen-binding fragment of any of        embodiments 293, 321-326, provided that the X₃ of SEQ ID NO:        100150 is V.    -   331. The antibody or antigen-binding fragment of any of        embodiments 293, 321-330, provided that the X₄ of SEQ ID NO:        100150 is F.    -   332. The antibody or antigen-binding fragment of any of        embodiments 293, 321-330, provided that the X₄ of SEQ ID NO:        100150 is Y.    -   333. The antibody or antigen-binding fragment of any of        embodiments 293, 321-332, provided that the X₅ of SEQ ID NO:        100150 is I.    -   334. The antibody or antigen-binding fragment of any of        embodiments 293, 321-332, provided that the X₅ of SEQ ID NO:        100150 is M.    -   335. The antibody or antigen-binding fragment of any of        embodiments 293, 321-334, provided that the X₁ of SEQ ID NO:        100152 is L.    -   336. The antibody or antigen-binding fragment of any of        embodiments 293, 321-334, provided that the X₁ of SEQ ID NO:        100152 is M.    -   337. The antibody or antigen-binding fragment of any of        embodiments 293, 321-336, provided that the X₂ of SEQ ID NO:        100152 is E.    -   338. The antibody or antigen-binding fragment of any of        embodiments 293, 321-336, provided that the X₂ of SEQ ID NO:        100152 is I.    -   339. The antibody or antigen-binding fragment of any of        embodiments 293, 321-336, provided that the X₂ of SEQ ID NO:        100152 is K.    -   340. The antibody or antigen-binding fragment of any of        embodiments 293, 321-336, provided that the X₂ of SEQ ID NO:        100152 is L.    -   341. The antibody or antigen-binding fragment of any of        embodiments 293, 321-336, provided that the X₂ of SEQ ID NO:        100152 is M.    -   342. The antibody or antigen-binding fragment of any of        embodiments 293, 321-336, provided that the X₂ of SEQ ID NO:        100152 is Q.    -   343. The antibody or antigen-binding fragment of any of        embodiments 293, 321-336, provided that the X₂ of SEQ ID NO:        100152 is T.    -   344. The antibody or antigen-binding fragment of any of        embodiments 293, 321-336, provided that the X₂ of SEQ ID NO:        100152 is V.    -   345. The antibody or antigen-binding fragment of any of        embodiments 293, 321-336, provided that the X₂ of SEQ ID NO:        100152 is W.    -   346. The antibody or antigen-binding fragment of any of        embodiments 293, 321-336, provided that the X₂ of SEQ ID NO:        100152 is Y.    -   347. The antibody or antigen-binding fragment of any of        embodiments 293, 321-346, provided that the X₁ of SEQ ID NO:        100155 is Q.    -   348. The antibody or antigen-binding fragment of any of        embodiments 293, 321-346, provided that the X₁ of SEQ ID NO:        100155 is N.    -   349. The antibody or antigen-binding fragment of any of        embodiments 293, 321-348, provided that the X₂ of SEQ ID NO:        100155 is D.    -   350. The antibody or antigen-binding fragment of any of        embodiments 293, 321-348, provided that the X₂ of SEQ ID NO:        100155 is E.    -   351. The antibody or antigen-binding fragment of any of        embodiments 293, 321-348, provided that the X₂ of SEQ ID NO:        100155 is H.    -   352. The antibody or antigen-binding fragment of any of        embodiments 293, 321-348, provided that the X₂ of SEQ ID NO:        100155 is N.    -   353. The antibody or antigen-binding fragment of any of        embodiments 293, 321-348, provided that the X₂ of SEQ ID NO:        100155 is Q.    -   354. The antibody or antigen-binding fragment of any of        embodiments 293, 321-348, provided that the X₂ of SEQ ID NO:        100155 is S.    -   355. The antibody or antigen-binding fragment of any of        embodiments 293, 321-354, provided that the X₃ of SEQ ID NO:        100155 is A.    -   356. The antibody or antigen-binding fragment of any of        embodiments 293, 321-354, provided that the X₃ of SEQ ID NO:        100155 is G.    -   357. The antibody or antigen-binding fragment of any of        embodiments 293, 321-356, provided that the X₄ of SEQ ID NO:        100155 is D.    -   358. The antibody or antigen-binding fragment of any of        embodiments 293, 321-356, provided that the X₄ of SEQ ID NO:        100155 is F.    -   359. The antibody or antigen-binding fragment of any of        embodiments 293, 321-356, provided that the X₄ of SEQ ID NO:        100155 is K.    -   360. The antibody or antigen-binding fragment of any of        embodiments 293, 321-356, provided that the X₄ of SEQ ID NO:        100155 is N.    -   361. The antibody or antigen-binding fragment of any of        embodiments 293, 321-356, provided that the X₄ of SEQ ID NO:        100155 is R.    -   362. The antibody or antigen-binding fragment of any of        embodiments 293, 321-356, provided that the X₄ of SEQ ID NO:        100155 is S.    -   363. The antibody or antigen-binding fragment of any of        embodiments 293, 321-356, provided that the X₄ of SEQ ID NO:        100155 is T.    -   364. The antibody or antigen-binding fragment of any of        embodiments 293-363, provided that the antibody or        antigen-binding fragment specifically binds to human TL1A.    -   365. The antibody or antigen-binding fragment of embodiment 364,        provided that the antibody or antigen-binding fragment        specifically binds to human TL1A with a K_(d) of 1×10⁻⁹ M or        less.    -   366. The antibody or antigen-binding fragment of embodiment 365,        provided that the K_(d) is measured using a method selected from        a standard ELISA assay and SPR.    -   367. The antibody or antigen-binding fragment of any of        embodiments 293-366, provided that the antibody or        antigen-binding fragment inhibits binding of DR3 to human TL1A.    -   368. The antibody or antigen-binding fragment of any of        embodiments 293-367, provided that the antibody or        antigen-binding fragment inhibits binding of DcR3 to human TL1A.    -   369. The antibody or antigen-binding fragment of any of        embodiments 293-368, provided that the antibody or        antigen-binding fragment is a humanized antibody, a CDR-grafted        antibody, a chimeric antibody, a Fab, a ScFv, or a combination        thereof.    -   370. The antibody or antigen-binding fragment of any of        embodiments 293-369, comprising a human CH1 domain.    -   371. The antibody or antigen-binding fragment of any of        embodiments 293-370, comprising a human CH2 domain.    -   372. The antibody or antigen-binding fragment of embodiment 371,        provided that that CH2 domain comprises at least one mutation        selected from L234A, L235A, and G237A, as numbered using Kabat.    -   373. The antibody or antigen-binding fragment of any of        embodiments 293-372, comprising a human CH3 domain.    -   374. A pharmaceutical composition comprising a therapeutically        effective amount of the antibody or antigen-binding fragment of        any of embodiments 293-373, and a pharmaceutically acceptable        carrier.    -   375. A method of treating an inflammatory disease in a subject        in need thereof, comprising administering to the subject a        therapeutically effective amount of the antibody or        antigen-binding fragment of any of embodiments 293-373.    -   376. The method of embodiment 375, provided that the        inflammatory disease is inflammatory bowel disease.    -   377. The method of embodiment 376, provided that the        inflammatory bowel disease comprises Crohn's disease.    -   378. The method of embodiment 377, provided that the subject has        been determined to be non-responsive to anti-TNF alpha therapy.    -   379. The method of embodiment 377 or embodiment 378, provided        that the subject has been determined to comprise a disease        phenotype comprising non-structuring/non-penetrating,        structuring, structuring and penetrating, or isolated internal        penetrating.    -   380. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising: a heavy chain variable region        comprising three heavy chain complementarity-determining regions        (HCDR1, HCDR2, and HCDR3) comprising        -   (a) a HCDR1 selected from: (i) a HCDR1 comprising SEQ ID NO:            1009, (ii) a HCDR1 comprising SEQ ID NO: 100150, wherein X₁            is selected from D and E, X₂ is selected from I, P and V, X₃            is selected from G, Q, S, and V, X₄ is selected from F and            Y, and X₅ is selected from I and M, (iii) a HCDR1 selected            from SEQ ID NOS: 100200-100295, and (iv) a HCDR1 comprising            an amino acid sequence that differs from a sequence selected            from the group consisting of SEQ ID NOS: 1009, 100150 and            100200-100295 by up to five, four, three, or two amino            acids,        -   (b) a HCDR2 selected from: (i) a HCDR2 comprising SEQ ID NO:            10012, and (ii) a HCDR2 comprising an amino acid sequence            that differs from SEQ ID NO: 10012 by up to five, four,            three, or two amino acids, and        -   (c) a HCDR3 selected from (i) a HCDR3 comprising SEQ ID NO:            10015, (ii) a HCDR3 comprising SEQ ID NO: 100152, wherein X₁            is selected from L and M, and X₂ is selected from E, I, K,            L, M, Q, T, V, W, and Y, (iii) a HCDR3 selected from SEQ ID            NOS: 100296-100314, and (iv) a HCDR3 comprising an amino            acid sequence that differs from a sequence selected from the            group consisting of SEQ ID NOS: 10015, 100152 and            100296-100314 by up to five, four, three, or two amino            acids; and    -   a light chain variable region comprising three light chain        complementarity-determining regions (LCDR1, LCDR2, and LCDR3)        comprising:        -   (a) a LCDR1 selected from: (i) a LCDR1 comprising SEQ ID NO:            10018, and (ii) a LCDR1 comprising an amino acid sequence            that differs from SEQ ID NO: 10018 by up to five, four,            three, or two amino acids,        -   (b) a LCDR2 selected from: (i) a LCDR2 comprising SEQ ID NO:            10021, and (ii) a LCDR2 comprising an amino acid sequence            that differs from SEQ ID NO: 10021 by up to five, four,            three, or two amino acids, and        -   (c) a LCDR3 selected from (i) a LCDR3 comprising SEQ ID NO:            10024, (ii) a LCDR3 comprising SEQ ID NO: 100155, wherein X₁            is selected from Q and N, X₂ is selected from D, E, H, N, Q,            and S, X₃ is selected from A and G, and X₄ is selected from            D, F, K, N, R, S, and T, (iii) a LCDR3 selected from SEQ ID            NOS: 100315-100482, and (iv) a LCDR3 comprising an amino            acid sequence that differs from a sequence selected from the            group consisting of SEQ ID NOS: 10024, 100155, and            100315-100482 by up to five, four, three, or two amino            acids.    -   381. The antibody or antigen-binding fragment of embodiment 380,        provided that the HCDR1 comprises SEQ ID NO: 100150, the HCDR2        comprises SEQ ID NO: 10012, the HCDR3 comprises SEQ ID NO:        100152, the LCDR1 comprises SEQ ID NO: 10018, the LCDR2        comprises SEQ ID NO: 10021, and the LCDR3 comprises SEQ ID NO:        100155.    -   382. The antibody or antigen-binding fragment of embodiment 380        or embodiment 381, provided that the X₁ of SEQ ID NO: 100150 is        D.    -   383. The antibody or antigen-binding fragment of embodiment 380        or embodiment 381 provided that the X₁ of SEQ ID NO: 100150 is        E.    -   384. The antibody or antigen-binding fragment of any of        embodiments 380-383, provided that the X₂ of SEQ ID NO: 100150        is I.    -   385. The antibody or antigen-binding fragment of any of        embodiments 380-383, provided that the X₂ of SEQ ID NO: 100150        is P.    -   386. The antibody or antigen-binding fragment of any of        embodiments 380-383, provided that the X₂ of SEQ ID NO: 100150        is V.    -   387. The antibody or antigen-binding fragment of any of        embodiments 380-386, provided that the X₃ of SEQ ID NO: 100150        is G.    -   388. The antibody or antigen-binding fragment of any of        embodiments 380-386, provided that the X₃ of SEQ ID NO: 100150        is Q.    -   389. The antibody or antigen-binding fragment of any of        embodiments 380-386, provided that the X₃ of SEQ ID NO: 100150        is S.    -   390. The antibody or antigen-binding fragment of any of        embodiments 380-386, provided that the X₃ of SEQ ID NO: 100150        is V.    -   391. The antibody or antigen-binding fragment of any of        embodiments 380-390, provided that the X₄ of SEQ ID NO: 100150        is F.    -   392. The antibody or antigen-binding fragment of any of        embodiments 380-390, provided that the X₄ of SEQ ID NO: 100150        is Y.    -   393. The antibody or antigen-binding fragment of any of        embodiments 380-392, provided that the X₅ of SEQ ID NO: 100150        is I.    -   394. The antibody or antigen-binding fragment of any of        embodiments 380-392, provided that the X₅ of SEQ ID NO: 100150        is M.    -   395. The antibody or antigen-binding fragment of any of        embodiments 380-394, provided that the X₁ of SEQ ID NO: 100152        is L.    -   396. The antibody or antigen-binding fragment of any of        embodiments 380-394, provided that the X₁ of SEQ ID NO: 100152        is M.    -   397. The antibody or antigen-binding fragment of any of        embodiments 380-396, provided that the X₂ of SEQ ID NO: 100152        is E.    -   398. The antibody or antigen-binding fragment of any of        embodiments 380-396, provided that the X₂ of SEQ ID NO: 100152        is I.    -   399. The antibody or antigen-binding fragment of any of        embodiments 380-396, provided that the X₂ of SEQ ID NO: 100152        is K.    -   400. The antibody or antigen-binding fragment of any of        embodiments 380-396, provided that the X₂ of SEQ ID NO: 100152        is L.    -   401. The antibody or antigen-binding fragment of any of        embodiments 380-396, provided that the X₂ of SEQ ID NO: 100152        is M.    -   402. The antibody or antigen-binding fragment of any of        embodiments 380-396, provided that the X₂ of SEQ ID NO: 100152        is Q.    -   403. The antibody or antigen-binding fragment of any of        embodiments 380-396, provided that the X₂ of SEQ ID NO: 100152        is T.    -   404. The antibody or antigen-binding fragment of any of        embodiments 380-396, provided that the X₂ of SEQ ID NO: 100152        is V.    -   405. The antibody or antigen-binding fragment of any of        embodiments 380-396, provided that the X₂ of SEQ ID NO: 100152        is W.    -   406. The antibody or antigen-binding fragment of any of        embodiments 380-396, provided that the X₂ of SEQ ID NO: 100152        is Y.    -   407. The antibody or antigen-binding fragment of any of        embodiments 380-406, provided that the X₁ of SEQ ID NO: 100155        is Q.    -   408. The antibody or antigen-binding fragment of any of        embodiments 380-406, provided that the X₁ of SEQ ID NO: 100155        is N.    -   409. The antibody or antigen-binding fragment of any of        embodiments 380-408, provided that the X₂ of SEQ ID NO: 100155        is D.    -   410. The antibody or antigen-binding fragment of any of        embodiments 380-408, provided that the X₂ of SEQ ID NO: 100155        is E.    -   411. The antibody or antigen-binding fragment of any of        embodiments 380-408, provided that the X₂ of SEQ ID NO: 100155        is H.    -   412. The antibody or antigen-binding fragment of any of        embodiments 380-408, provided that the X₂ of SEQ ID NO: 100155        is N.    -   413. The antibody or antigen-binding fragment of any of        embodiments 380-408, provided that the X₂ of SEQ ID NO: 100155        is Q.    -   414. The antibody or antigen-binding fragment of any of        embodiments 380-408, provided that the X₂ of SEQ ID NO: 100155        is S.    -   415. The antibody or antigen-binding fragment of any of        embodiments 380-414, provided that the X₃ of SEQ ID NO: 100155        is A.    -   416. The antibody or antigen-binding fragment of any of        embodiments 380-414, provided that the X₃ of SEQ ID NO: 100155        is G.    -   417. The antibody or antigen-binding fragment of any of        embodiments 380-416, provided that the X₄ of SEQ ID NO: 100155        is D.    -   418. The antibody or antigen-binding fragment of any of        embodiments 380-416, provided that the X₄ of SEQ ID NO: 100155        is F.    -   419. The antibody or antigen-binding fragment of any of        embodiments 380-416, provided that the X₄ of SEQ ID NO: 100155        is K.    -   420. The antibody or antigen-binding fragment of any of        embodiments 380-416, provided that the X₄ of SEQ ID NO: 100155        is N.    -   421. The antibody or antigen-binding fragment of any of        embodiments 380-416, provided that the X₄ of SEQ ID NO: 100155        is R.    -   422. The antibody or antigen-binding fragment of any of        embodiments 380-416, provided that the X₄ of SEQ ID NO: 100155        is S.    -   423. The antibody or antigen-binding fragment of any of        embodiments 380-416, provided that the X₄ of SEQ ID NO: 100155        is T.    -   424. The antibody or antigen-binding fragment of any of        embodiments 380-423, provided that the antibody or        antigen-binding fragment specifically binds to human TL1A.    -   425. The antibody or antigen-binding fragment of embodiment 424,        provided that the antibody or antigen-binding fragment        specifically binds to human TL1A with a K_(d) of 1×10⁻⁹ M or        less.    -   426. The antibody or antigen-binding fragment of embodiment 425,        provided that the K_(d) is measured using a method selected from        a standard ELISA assay and SPR.    -   427. The antibody or antigen-binding fragment of any of        embodiments 380-426, provided that the antibody or        antigen-binding fragment inhibits binding of DR3 to human TL1A.    -   428. The antibody or antigen-binding fragment of any of        embodiments 380-427, provided that the antibody or        antigen-binding fragment inhibits binding of DcR3 to human TL1A.    -   429. The antibody or antigen-binding fragment of any of        embodiments 380-428, provided that the antibody or        antigen-binding fragment is a humanized antibody, a CDR-grafted        antibody, a chimeric antibody, a Fab, a ScFv, or a combination        thereof.    -   430. The antibody or antigen-binding fragment of any of        embodiments 380-429, comprising a human CH1 domain.    -   431. The antibody or antigen-binding fragment of any of        embodiments 380-430, comprising a human CH2 domain.    -   432. The antibody or antigen-binding fragment of embodiment 431,        provided that that CH2 domain comprises at least one mutation        selected from L234A, L235A, and G237A, as numbered using Kabat.    -   433. The antibody or antigen-binding fragment of any of        embodiments 380-432, comprising a human CH3 domain.    -   434. A pharmaceutical composition comprising a therapeutically        effective amount of the antibody or antigen-binding fragment of        any of embodiments 380-433, and a pharmaceutically acceptable        carrier.    -   435. A method of treating an inflammatory disease in a subject        in need thereof, comprising administering to the subject a        therapeutically effective amount of the antibody or        antigen-binding fragment of any of embodiments 380-433.    -   436. The method of embodiment 435, provided that the        inflammatory disease is inflammatory bowel disease.    -   437. The method of embodiment 436, provided that the        inflammatory bowel disease comprises Crohn's disease.    -   438. The method of embodiment 437, provided that the subject has        been determined to be non-responsive to anti-TNF alpha therapy.    -   439. The method of embodiment 437 or embodiment 438, provided        that the subject has been determined to comprise a disease        phenotype comprising non-structuring/non-penetrating,        structuring, structuring and penetrating, or isolated internal        penetrating.    -   440. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising: a heavy chain variable region        comprising SEQ ID NO: 10052 or SEQ ID NO: 10054, and a light        chain variable region comprising SEQ ID NO: 10053.    -   441. The antibody or antigen-binding fragment of embodiment 440,        provided that the heavy chain variable region comprises SEQ ID        NO: 10052.    -   442. The antibody or antigen-binding fragment of embodiment 440,        provided that the heavy chain variable region comprises SEQ ID        NO: 10054.    -   443. The antibody or antigen-binding fragment of any of        embodiments 440-442, provided that the X₁ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is D.    -   444. The antibody or antigen-binding fragment of any of        embodiments 440-442 provided that the X₁ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is E.    -   445. The antibody or antigen-binding fragment of any of        embodiments 440-444, provided that the X₂ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is I.    -   446. The antibody or antigen-binding fragment of any of        embodiments 440-444, provided that the X₂ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is P.    -   447. The antibody or antigen-binding fragment of any of        embodiments 440-444, provided that the X₂ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is V.    -   448. The antibody or antigen-binding fragment of any of        embodiments 440-447, provided that the X₃ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is G.    -   449. The antibody or antigen-binding fragment of any of        embodiments 440-447, provided that the X₃ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is Q.    -   450. The antibody or antigen-binding fragment of any of        embodiments 440-447, provided that the X₃ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is S.    -   451. The antibody or antigen-binding fragment of any of        embodiments 440-447, provided that the X₃ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is V.    -   452. The antibody or antigen-binding fragment of any of        embodiments 440-451, provided that the X₄ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is F.    -   453. The antibody or antigen-binding fragment of any of        embodiments 440-451, provided that the X₄ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is Y.    -   454. The antibody or antigen-binding fragment of any of        embodiments 440-453, provided that the X₅ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is I.    -   455. The antibody or antigen-binding fragment of any of        embodiments 440-453, provided that the X₅ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is M.    -   456. The antibody or antigen-binding fragment of any of        embodiments 440-455, provided that the X₆ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is L.    -   457. The antibody or antigen-binding fragment of any of        embodiments 440-455, provided that the X₆ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is M.    -   458. The antibody or antigen-binding fragment of any of        embodiments 440-457, provided that the X₇ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is E.    -   459. The antibody or antigen-binding fragment of any of        embodiments 440-457, provided that the X₇ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is I.    -   460. The antibody or antigen-binding fragment of any of        embodiments 440-457, provided that the X₇ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is K.    -   461. The antibody or antigen-binding fragment of any of        embodiments 440-457, provided that the X₇ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is L.    -   462. The antibody or antigen-binding fragment of any of        embodiments 440-457, provided that the X₇ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is M.    -   463. The antibody or antigen-binding fragment of any of        embodiments 440-457, provided that the X₇ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is Q.    -   464. The antibody or antigen-binding fragment of any of        embodiments 440-457, provided that the X₇ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is T.    -   465. The antibody or antigen-binding fragment of any of        embodiments 440-457, provided that the X₇ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is V.    -   466. The antibody or antigen-binding fragment of any of        embodiments 440-457, provided that the X₇ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is W.    -   467. The antibody or antigen-binding fragment of any of        embodiments 440-457, provided that the X₇ of SEQ ID NO: 10052 or        SEQ ID NO: 10054 is Y.    -   468. The antibody or antigen-binding fragment of any of        embodiments 440-467, provided that the X₁ of SEQ ID NO: 10053 is        Q.    -   469. The antibody or antigen-binding fragment of any of        embodiments 440-467, provided that the X₁ of SEQ ID NO: 10053 is        N.    -   470. The antibody or antigen-binding fragment of any of        embodiments 440-469, provided that the X₂ of SEQ ID NO: 10053 is        D.    -   471. The antibody or antigen-binding fragment of any of        embodiments 440-469, provided that the X₂ of SEQ ID NO: 10053 is        E.    -   472. The antibody or antigen-binding fragment of any of        embodiments 440-469, provided that the X₂ of SEQ ID NO: 10053 is        H.    -   473. The antibody or antigen-binding fragment of any of        embodiments 440-469, provided that the X₂ of SEQ ID NO: 10053 is        N.    -   474. The antibody or antigen-binding fragment of any of        embodiments 440-469, provided that the X₂ of SEQ ID NO: 10053 is        Q.    -   475. The antibody or antigen-binding fragment of any of        embodiments 440-469, provided that the X₂ of SEQ ID NO: 10053 is        S.    -   476. The antibody or antigen-binding fragment of any of        embodiments 440-475, provided that the X₃ of SEQ ID NO: 10053 is        A.    -   477. The antibody or antigen-binding fragment of any of        embodiments 440-475, provided that the X₃ of SEQ ID NO: 10053 is        G.    -   478. The antibody or antigen-binding fragment of any of        embodiments 440-477, provided that the X₄ of SEQ ID NO: 10053 is        D.    -   479. The antibody or antigen-binding fragment of any of        embodiments 440-477, provided that the X₄ of SEQ ID NO: 10053 is        F.    -   480. The antibody or antigen-binding fragment of any of        embodiments 440-477, provided that the X₄ of SEQ ID NO: 10053 is        K.    -   481. The antibody or antigen-binding fragment of any of        embodiments 440-477, provided that the X₄ of SEQ ID NO: 10053 is        N.    -   482. The antibody or antigen-binding fragment of any of        embodiments 440-477, provided that the X₄ of SEQ ID NO: 10053 is        R.    -   483. The antibody or antigen-binding fragment of any of        embodiments 440-477, provided that the X₄ of SEQ ID NO: 10053 is        S.    -   484. The antibody or antigen-binding fragment of any of        embodiments 440-477, provided that the X₄ of SEQ ID NO: 10053 is        T.    -   485. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising: a heavy chain variable region of SEQ        ID NO: 10036, and a light chain variable region of SEQ ID NO:        10038.    -   486. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising: a heavy chain variable region of SEQ        ID NO: 10040, and a light chain variable region of SEQ ID NO:        10042.    -   487. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising: a heavy chain variable region of SEQ        ID NO: 10040, and a light chain variable region of SEQ ID NO:        10038.    -   488. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising: a heavy chain variable region of SEQ        ID NO: 10044, and a light chain variable region of SEQ ID NO:        10038.    -   489. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising: a heavy chain variable region of SEQ        ID NO: 10043, and a light chain variable region of SEQ ID NO:        10038.    -   490. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising: a heavy chain variable region of SEQ        ID NO: 10045, and a light chain variable region of SEQ ID NO:        10038.    -   491. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising: a heavy chain variable region of SEQ        ID NO: 10046, and a light chain variable region of SEQ ID NO:        10038.    -   492. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising: a heavy chain variable region of SEQ        ID NO: 10040, and a light chain variable region of SEQ ID NO:        10047.    -   493. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising: a heavy chain variable region of SEQ        ID NO: 10040, and a light chain variable region of SEQ ID NO:        10048.    -   494. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising: a heavy chain variable region of SEQ        ID NO: 10040, and a light chain variable region of SEQ ID NO:        10049.    -   495. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising: a heavy chain variable region of SEQ        ID NO: 10040, and a light chain variable region of SEQ ID NO:        10050.    -   496. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising: a heavy chain variable region of SEQ        ID NO: 10040, and a light chain variable region of SEQ ID NO:        10051.    -   497. The antibody or antigen-binding fragment of any of        embodiments 440-496, provided that the antibody or        antigen-binding fragment specifically binds to human TL1A.    -   498. The antibody or antigen-binding fragment of embodiment 497,        provided that the antibody or antigen-binding fragment        specifically binds to human TL1A with a K_(d) of 1×10⁻⁹ M or        less.    -   499. The antibody or antigen-binding fragment of embodiment 498,        provided that the K_(d) is measured using a method selected from        a standard ELISA assay and SPR.    -   500. The antibody or antigen-binding fragment of any of        embodiments 440-499, provided that the antibody or        antigen-binding fragment inhibits binding of DR3 to human TL1A.    -   501. The antibody or antigen-binding fragment of any of        embodiments 440-500, provided that the antibody or        antigen-binding fragment inhibits binding of DcR3 to human TL1A.    -   502. The antibody or antigen-binding fragment of any of        embodiments 440-501, provided that the antibody or        antigen-binding fragment is a humanized antibody, a CDR-grafted        antibody, a chimeric antibody, a Fab, a ScFv, or a combination        thereof.    -   503. The antibody or antigen-binding fragment of any of        embodiments 440-502, comprising a human CH1 domain.    -   504. The antibody or antigen-binding fragment of any of        embodiments 440-503, comprising a human CH2 domain.    -   505. The antibody or antigen-binding fragment of embodiment 504,        provided that that CH2 domain comprises at least one mutation        selected from L234A, L235A, and G237A, as numbered using Kabat.    -   506. The antibody or antigen-binding fragment of any of        embodiments 440-505, comprising a human CH3 domain.    -   507. A pharmaceutical composition comprising a therapeutically        effective amount of the antibody or antigen-binding fragment of        any of embodiments 440-506, and a pharmaceutically acceptable        carrier.    -   508. A method of treating an inflammatory disease in a subject        in need thereof, comprising administering to the subject a        therapeutically effective amount of the antibody or        antigen-binding fragment of any of embodiments 440-506.    -   509. The method of embodiment 508, provided that the        inflammatory disease is inflammatory bowel disease.    -   510. The method of embodiment 509, provided that the        inflammatory bowel disease comprises Crohn's disease.    -   511. The method of embodiment 510, provided that the subject has        been determined to be non-responsive to anti-TNF alpha therapy.    -   512. The method of embodiment 510 or embodiment 511, provided        that the subject has been determined to comprise a disease        phenotype comprising non-structuring/non-penetrating,        structuring, structuring and penetrating, or isolated internal        penetrating.    -   513. An antibody or antigen binding fragment that binds to the        same region of human TL1A as a reference antibody of any of        embodiments 1-112, 119-199, 206-286, 293-373, 380-433, and        440-506.    -   514. An antibody or antigen binding fragment that binds to the        same region of human TL1A as a reference antibody comprising a        heavy chain variable region of SEQ ID NO: 10036, and a light        chain variable region of SEQ ID NO: 10038.    -   515. An antibody or antigen binding fragment that binds to the        same region of human TL1A as a reference antibody comprising a        heavy chain variable region of SEQ ID NO: 10040, and a light        chain variable region of SEQ ID NO: 10042.    -   516. An antibody or antigen binding fragment that binds to the        same region of human TL1A as a reference antibody comprising a        heavy chain variable region of SEQ ID NO: 10040, and a light        chain variable region of SEQ ID NO: 10038.    -   517. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising: a heavy chain variable region        comprising:        -   (a) an HCDR1 comprising an amino acid sequence set forth by            SEQ ID NO: 553;        -   (b) an HCDR2 comprising an amino acid sequence set forth by            any one of SEQ ID NOs: 554 to 564 or 574 to 577; and        -   (c) an HCDR3 comprising an amino acid sequence set forth by            any one of SEQ ID NOs: 565 to 568 or 578 to 581; and    -   a light chain variable region comprising:        -   (d) an LCDR1 comprising an amino acid sequence set forth by            any one of SEQ ID NOs: 569 or 570;        -   (e) an LCDR2 comprising an amino acid sequence set forth by            SEQ ID NO: 488; and        -   (f) an LCDR3 comprising an amino acid sequence set forth by            any one of SEQ ID NOs: 571 to 573 or 582 to 585.    -   518. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising:        -   a heavy chain variable region comprising:            -   (a) an HCDR1 comprising an amino acid sequence set forth                by SEQ ID NO: 553;            -   (b) an HCDR2 comprising an amino acid sequence set forth                by SEQ ID NO: 559; and            -   (c) an HCDR3 comprising an amino acid sequence set forth                by SEQ ID NO: 567; and        -   a light chain variable region comprising:            -   (d) an LCDR1 comprising an amino acid sequence set forth                by SEQ ID NO: 569;            -   (e) an LCDR2 comprising an amino acid sequence set forth                by SEQ ID NO: 488; and            -   (f) an LCDR3 comprising an amino acid sequence set forth                by any one of SEQ ID NO: 573.    -   519. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising:        -   a heavy chain variable region comprising:            -   (a) an HCDR1 comprising an amino acid sequence set forth                by SEQ ID NO: 553;            -   (b) an HCDR2 comprising an amino acid sequence set forth                by SEQ ID NO: 563; and            -   (c) an HCDR3 comprising an amino acid sequence set forth                by SEQ ID NO: 568; and        -   a light chain variable region comprising:            -   (d) an LCDR1 comprising an amino acid sequence set forth                by SEQ ID NO: 569;            -   (e) an LCDR2 comprising an amino acid sequence set forth                by SEQ ID NO: 488; and            -   (f) an LCDR3 comprising an amino acid sequence set forth                by any one of SEQ ID NO: 572.    -   520. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising:        -   a heavy chain variable region comprising:            -   (a) an HCDR1 comprising an amino acid sequence set forth                by SEQ ID NO: 553;            -   (b) an HCDR2 comprising an amino acid sequence set forth                by SEQ ID NO: 555; and            -   (c) an HCDR3 comprising an amino acid sequence set forth                by SEQ ID NO: 566; and        -   a light chain variable region comprising:            -   (d) an LCDR1 comprising an amino acid sequence set forth                by SEQ ID NO: 569;            -   (e) an LCDR2 comprising an amino acid sequence set forth                by SEQ ID NO: 488; and            -   (f) an LCDR3 comprising an amino acid sequence set forth                by any one of SEQ ID NO: 572.    -   521. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising:        -   a heavy chain variable region comprising:            -   (a) an HCDR1 comprising an amino acid sequence set forth                by SEQ ID NO: 553;            -   (b) an HCDR2 comprising an amino acid sequence set forth                by SEQ ID NO: 558; and            -   (c) an HCDR3 comprising an amino acid sequence set forth                by SEQ ID NO: 566; and        -   a light chain variable region comprising:            -   (d) an LCDR1 comprising an amino acid sequence set forth                by SEQ ID NO: 569;            -   (e) an LCDR2 comprising an amino acid sequence set forth                by SEQ ID NO: 488; and            -   (f) an LCDR3 comprising an amino acid sequence set forth                by any one of SEQ ID NO: 572.    -   522. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising:        -   a heavy chain variable region comprising:            -   (a) an HCDR1 comprising an amino acid sequence set forth                by SEQ ID NO: 553;            -   (b) an HCDR2 comprising an amino acid sequence set forth                by SEQ ID NO: 564; and            -   (c) an HCDR3 comprising an amino acid sequence set forth                by SEQ ID NO: 568; and        -   a light chain variable region comprising:            -   (d) an LCDR1 comprising an amino acid sequence set forth                by SEQ ID NO: 569;            -   (e) an LCDR2 comprising an amino acid sequence set forth                by SEQ ID NO: 488; and            -   (f) an LCDR3 comprising an amino acid sequence set forth                by any one of SEQ ID NO: 572.    -   523. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising:        -   (a) a heavy chain variable region comprising an HCDR1, an            HCDR2, and an HCDR3 from any one of SEQ ID NOs: 491, 493,            495, 497, 499, 501, 503, 505, 507, 509, 511, 513, 515, 517,            519, 521, 523, 525, 527, 529, 531, 533, 535, 537, 539, or            541; and        -   (b) a light chain variable region comprising an LCDR1, an            LCDR2, and an LCDR3 from any one of SEQ ID NOs: 490, 492,            494, 496, 498, 500, 502, 504, 506, 508, 510, 512, 514, 516,            518, 520, 522, 524, 526, 528, 530, 532, 534, 536, 538, or            540; wherein the CDRs are defined by the Kabat, Chothia, or            IMGT method or a combination thereof.    -   524. The antibody or antigen-binding fragment of any one of        embodiments 517 to 523, comprising a human heavy chain framework        region 1 that is at least 90%, 95%, 96%, 97%, 98%, 99% identical        to that set forth is SEQ ID NO: 545.    -   525. The antibody or antigen-binding fragment of any one of        embodiments 517 to 524, comprising a human heavy chain framework        region 2 that is at least 90%, 95%, 96%, 97%, 98%, 99% identical        to that set forth is SEQ ID NO: 546.    -   526. The antibody or antigen-binding fragment of any one of        embodiments 517 to 525, comprising a human heavy chain framework        region 3 that is at least 90%, 95%, 96%, 97%, 98%, 99% identical        to that set forth is SEQ ID NO: 547 or 586 to 588.    -   527. The antibody or antigen-binding fragment of any one of        embodiments 517 to 526, comprising a human heavy chain framework        region 4 that is at least 90%, 95%, 96%, 97%, 98%, 99% identical        to that set forth is SEQ ID NO: 548.    -   528. The antibody or antigen-binding fragment of any one of        embodiments 517 to 527, comprising a human light chain framework        region 1 that is at least 90%, 95%, 96%, 97%, 98%, 99% identical        to that set forth is SEQ ID NO: 549.    -   529. The antibody or antigen-binding fragment of any one of        embodiments 517 to 528, comprising a human light chain framework        region 2 that is at least 90%, 95%, 96%, 97%, 98%, 99% identical        to that set forth is SEQ ID NO: 550.    -   530. The antibody or antigen-binding fragment of any one of        embodiments 517 to 529, comprising a human light chain framework        region 3 that is at least 90%, 95%, 96%, 97%, 98%, 99% identical        to that set forth is SEQ ID NO: 551.    -   531. The antibody or antigen-binding fragment of any one of        embodiments 517 to 530, comprising a human light chain framework        region 4 that is at least 90%, 95%, 96%, 97%, 98%, 99% identical        to that set forth is SEQ ID NO: 552.    -   532. The antibody or antigen-binding fragment of any one of        embodiments 517 to 531, comprising:        -   (a) a human heavy chain framework region 1 that is at least            90% identical to that set forth is SEQ ID NO: 545;        -   (b) a human heavy chain framework region 2 that is at least            90% identical to that set forth is SEQ ID NO: 546;        -   (c) a human heavy chain framework region 3 that is at least            90% identical to that set forth is SEQ ID NO: 547 or 586 to            588;        -   (d) a human heavy chain framework region 4 that is at least            90% identical to that set forth is SEQ ID NO: 548;        -   (e) a human light chain framework region 1 that is at least            90% identical to that set forth is SEQ ID NO: 549;        -   (f) a human light chain framework region 2 that is at least            90% identical to that set forth is SEQ ID NO: 550;        -   (g) a human light chain framework region 3 that is at least            90% identical to that set forth is SEQ ID NO: 551; and        -   (h) a human light chain framework region 4 that is at least            90% identical to that set forth is SEQ ID NO: 552.    -   533. The antibody or antigen-binding fragment of embodiment 532,        comprising:        -   (a) a human heavy chain framework region 1 that is at least            95% identical to that set forth is SEQ ID NO: 545;        -   (b) a human heavy chain framework region 2 that is at least            95% identical to that set forth is SEQ ID NO: 546;        -   (c) a human heavy chain framework region 3 that is at least            95% identical to that set forth is SEQ ID NO: 547 or 586 to            588;        -   (d) a human heavy chain framework region 4 that is at least            95% identical to that set forth is SEQ ID NO: 548;        -   (e) a human light chain framework region 1 that is at least            95% identical to that set forth is SEQ ID NO: 549;        -   (f) a human light chain framework region 2 that is at least            95% identical to that set forth is SEQ ID NO: 550;        -   (g) a human light chain framework region 3 that is at least            95% identical to that set forth is SEQ ID NO: 551; and        -   (h) a human light chain framework region 4 that is at least            95% identical to that set forth is SEQ ID NO: 552.    -   534. The antibody or antigen-binding fragment of embodiments        532, comprising: (a) a human heavy chain framework region 1 that        is at least 97% identical to that set forth is SEQ ID NO: 545;        -   (b) a human heavy chain framework region 2 that is at least            97% identical to that set forth is SEQ ID NO: 546;        -   (c) a human heavy chain framework region 3 that is at least            97% identical to that set forth is SEQ ID NO: 547 or 586 to            588;        -   (d) a human heavy chain framework region 4 that is at least            97% identical to that set forth is SEQ ID NO: 548;        -   (e) a human light chain framework region 1 that is at least            97% identical to that set forth is SEQ ID NO: 549;        -   (f) a human light chain framework region 2 that is at least            97% identical to that set forth is SEQ ID NO: 550;        -   (g) a human light chain framework region 3 that is at least            97% identical to that set forth is SEQ ID NO: 551; and        -   (h) a human light chain framework region 4 that is at least            97% identical to that set forth is SEQ ID NO: 552.    -   535. The antibody or antigen-binding fragment of embodiment 532,        comprising:        -   (a) a human heavy chain framework region 1 that is at least            98% identical to that set forth is SEQ ID NO: 545;        -   (b) a human heavy chain framework region 2 that is at least            98% identical to that set forth is SEQ ID NO: 546;        -   (c) a human heavy chain framework region 3 that is at least            98% identical to that set forth is SEQ ID NO: 547 or 586 to            588;        -   (d) a human heavy chain framework region 4 that is at least            98% identical to that set forth is SEQ ID NO: 548;        -   (e) a human light chain framework region 1 that is at least            98% identical to that set forth is SEQ ID NO: 549;        -   (f) a human light chain framework region 2 that is at least            98% identical to that set forth is SEQ ID NO: 550;        -   (g) a human light chain framework region 3 that is at least            98% identical to that set forth is SEQ ID NO: 551; and        -   (h) a human light chain framework region 4 that is at least            98% identical to that set forth is SEQ ID NO: 552.    -   536. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising:        -   (a) a heavy chain variable region comprising an amino acid            sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or            100% identical to any one of SEQ ID NOs: 491, 493, 495, 497,            499, 501, 503, 505, 507, 509, 511, 513, 515, 517, 519, 521,            523, 525, 527, 529, 531, 533, 535, 537, 539, or 541; and        -   (b) a light chain variable region comprising an amino acid            sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or            100% identical to any one of SEQ ID NOs: 490, 492, 494, 496,            498, 500, 502, 504, 506, 508, 510, 512, 514, 516, 518, 520,            522, 524, 526, 528, 530, 532, 534, 536, 538, or 540.    -   537. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising:        -   (a) a heavy chain variable region comprising an amino acid            sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or            100% identical to SEQ ID NO: 503; and        -   (b) a light chain variable region comprising an amino acid            sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or            100% identical to SEQ ID NO: 502.    -   538. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising:        -   (a) a heavy chain variable region comprising an amino acid            sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or            100% identical to SEQ ID NO: 511; and        -   (b) a light chain variable region comprising an amino acid            sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or            100% identical to SEQ ID NO: 510.    -   539. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising:        -   (a) a heavy chain variable region comprising an amino acid            sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or            100% identical to SEQ ID NO: 493; and        -   (b) a light chain variable region comprising an amino acid            sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or            100% identical to SEQ ID NO: 492.    -   540. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising:        -   (a) a heavy chain variable region comprising an amino acid            sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or            100% identical to SEQ ID NO: 501; and        -   (b) a light chain variable region comprising an amino acid            sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or            100% identical to SEQ ID NO: 500.    -   541. An antibody or antigen-binding fragment that specifically        binds to TL1A, comprising:        -   (a) a heavy chain variable region comprising an amino acid            sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or            100% identical to SEQ ID NO: 515; and        -   (b) a light chain variable region comprising an amino acid            sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or            100% identical to SEQ ID NO: 514.    -   542. The antibody or antigen-binding fragment of any one of        embodiments 517 to 541, wherein the antibody or antigen-binding        fragment is chimeric or humanized.    -   543. The antibody or antigen-binding fragment of any one of        embodiments 517 to 541, wherein the antibody or antigen-binding        fragment is an IgG antibody.    -   544. The antibody or antigen-binding fragment of any one of        embodiments 517 to 541, wherein the antibody or antigen-binding        fragment comprises a Fab, F(ab)₂, a single-domain antibody, a        single chain variable fragment (scFv), or a nanobody.    -   545. The antibody or antigen-binding fragment of any one of        embodiments 517 to 544, comprising a heavy chain constant region        comprising an amino acid sequence as set forth by SEQ ID NO: 542        or 543.    -   546. The antibody or antigen-binding fragment of any one of        embodiments 517 to 544, comprising a heavy chain constant region        comprising an amino acid sequence as set forth by SEQ ID NO:        542.    -   547. The antibody or antigen-binding fragment of any one of        embodiments 517 to 544, comprising a light chain constant region        comprising an amino acid sequence as set forth by SEQ ID NO:        544.

In certain embodiments, the antibody or antigen binding fragmentcomprises (a) a heavy chain variable region comprising an amino acidsequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100% identicalto any one of SEQ ID NOs: 491, 493, 495, 497, 499, 501, 503, 505, 507,509, 511, 513, 515, 517, 519, 521, 523, 525, 527, 529, 531, 533, 535,537, 539, or 541; and (b) a light chain variable region comprising anamino acid sequence at least about 85%, 90%, 95%, 97%, 98%, 99%, or 100%identical to any one of SEQ ID NOs: 490, 492, 494, 496, 498, 500, 502,504, 506, 508, 510, 512, 514, 516, 518, 520, 522, 524, 526, 528, 530,532, 534, 536, 538, or 540.

Non-limiting methods for determining whether an anti-TL1A antibody bindsto the same region of a reference antibody are known in the art. Anexemplary method comprises a competition assay. For instance, the methodcomprises determining whether a reference antibody can compete withbinding between the reference antibody and the TL1A protein or portionthereof, or determining whether the reference antibody can compete withbinding between the reference antibody and the TL1A protein or portionthereof. Exemplary methods include use of surface plasmon resonance toevaluate whether an anti-TL1A antibody can compete with the bindingbetween TL1A and another anti-TL1A antibody. In some cases, surfaceplasmon resonance is utilized in the competition assay.

TABLE 2A Non-Limiting Examples of anti-TL1A and anti-DR3Antibodies and Portions Thereof SEQ ID Antibody Region Sequence   109HCDR1 GFTFSTYG   110 HCDR2 ISGTGRTT   111 HCDR3 TKERGDYYYG VFDY   112LCDR1 QTISSW   113 LCDR2 AAS   114 LCDR3 QQYHRSWT   115 HC VariableEVQLLESGGG LVQPGKSLRL SCAVSGFTFS TYGMNWVRQAPGKGLEWVSS ISGTGRTTYH ADSVQGRFTV SRDNSKNILYLQMNSLRADD TAVYFCTKER GDYYYGVFDY WGQGTLVTVS S   116 LC VariableDIQMTQSPST LSASVGDRVT ITCRASQTIS SWLAWYQQTPEKAPKLLIYA ASNLQSGVPS RFSGSGSGTE FTLTISSLQP DDFATYYCQQ YHRSWTFGQG TKVEIT  117 HCDR1 GFTFSSYW   118 HCDR2 IKEDGSEK   119 HCDR3 AREDYDSYYKYGMDV  120 LCDR1 QSILYSSNNK NY   121 LCDR2 WAS   122 LCDR3 QQYYSTPFT   123HC Variable EVQLVESGGG LVQPGGSLRL SCAVSGFTFS SYWMSWVRQAPGKGLEWVAN IKEDGSEKNY VDSVKGRFTL SSDNAKNSLYLQMNSLRAED TAVYYCARED YDSYYKYGMD VWGQGTAVIV SS   124 LC VariableDIVMTQSPDS LAVSLGERAT INCKSSQSIL YSSNNKNYLAWYQQKPGQPP KLLIYWASTR ESGVPDRFSG SGSGTDFTLTISSLQAEDVS VYYCQQYYST PFTFGPGTKV DIK   125 HCDR1 GGSFTGFY   126 HCDR2INHRGNT   127 HCDR3 ASPFYDFWSG SDY   128 LCDR1 QSLVHSDGNT Y   129 LCDR2KIS   130 LCDR3 MQATQFPLT   131 HC VariableQVQLQQWGAG LLKPSETLSL TCAVYGGSFT GFYWSWIRQPPGKGLEWIGE INHRGNTNYN PSLKSRVTMS VDTSKNQFSLNMISVTAADT AMYFCASPFY DFWSGSDYWG QGTLVTVSS   132 LC VariableDIMLTQTPLT SPVTLGQPAS ISCKSSQSLV HSDGNTYLSWLQQRPGQPPR LLFYKISNRF SGVPDRFSGS GAGTDFTLKISRVEAEDVGV YYCMQATQFP LTFGGGTKVE IK   133 HCDR1GY(X1)F(X2)(X3)YGIS; X1 = P, S, D, Q, N; X2 = T, R; X3 = N, T, Y, H  134 HCDR2 WIS(X1)YNG(X2)(X3)(X4) YA(X5)(X6)(X7)QG;X1 = T, P, S, A; X2 = N, G, V, K, A; X3 =T, K; X4 = H, N; X5 = Q, R; X6 = K, M; X7 = L, H   135 HCDR3ENYYGSG(X1)(X2)R GGMD(X3); X1 = S, A; X2 = Y, P; X3 = V, A, G   136HCDR1 GYDFTYYGIS   137 HCDR2 WISTYNGNTH YARMLQG   138 HCDR3ENYYGSGAYR GGMDV   139 LCDR1 RASQSVSSYL A   140 LCDR2 DASNRAT   141LCDR3 QQRSNWPWT   142 HC VariableQVQLVQSGAE VKKPGASVKV SCKASGYDFT YYGISWVRQAPGQGLEWMGW ISTYNGNTHY ARMLQGRVTM TTDTSTRTAYMELRSLRSDD TAVYYCAREN YYGSGAYRGG MDVWGQGTTV TVSS   143 LC VariableEIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKPGQAPRLLIYD ASNRATGIPA RFSGSGSGTD FTLTISSLEPEDFAVYYCQQ RSNWPWTFGQ GTKVEIK   144 HCQVQLVQSGAE VKKPGASVKV SCKASGYDFT YYGISWVRQAPGQGLEWMGW ISTYNGNTHY ARMLQGRVTM TTDTSTRTAYMELRSLRSDD TAVYYCAREN YYGSGAYRGG MDVWGQGTTVTVSSASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEPVTVSWNSGAL TSGVHTFPAV LQSSGLYSLS SVVTVPSSSLGTQTYICNVN HKPSNTKVDK KVEPKSCDKT HTCPPCPAPEAAGAPSVFLF PPKPKDTLMI SRTPEVTCVV VDVSHEDPEVKFNWYVDGVE VHNAKTKPRE EQYNSTYRVV SVLTVLHQDWLNGKEYKCKV SNKALPAPIE KTISKAKGQP REPQVYTLPPSREEMTKNQV SLTCLVKGFY PSDIAVEWES NGQPENNYKTTPPVLDSDGS FFLYSKLTVD KSRWQQGNVF SCSVMHEALH NHYTQKSLSL SPG   145 LCEIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKPGQAPRLLIYD ASNRATGIPA RFSGSGSGTD FTLTISSLEPEDFAVYYCQQ RSNWPWTFGQ GTKVEIKRTV AAPSVFIFPPSDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC   146 HCDR1SRSYYWG   147 HCDR2 SIYYNGRTYY NPSLKS   148 HCDR3 EDYGDYGAFD I   149LCDR1 RASQGISSAL A   150 LCDR2 DASSLES   151 LCDR3 QQFNSYPLT   152HC Variable QLQLQESGPG LVKPSETLSL TCTVSGGSIS SRSYYWGWIRQPPGKGLEWI GSIYYNGRTY YNPSLKSRVT ISVDTSKNQFSLKLSSVTAA DTAVYYCARE DYGDYGAFDI WGQGTMVTVS S   153 LC VariableAIQLTQSPSS LSASVGDRVT ITCRASQGIS SALAWYQQKPGKAPKLLIYD ASSLESGVPS RFSGSGSGTD FTLTISSLQPEDFATYYCQQ FNSYPLTFGG GTKVEIK   154 HCDR1 TSNMGVV   155 HCDR2HILWDDREYSNPALKS   156 HCDR3 MSRNYYGSSYVMDY   157 LCDR1 SASSSVNYMH   158LCDR2 STSNLAS   159 LCDR3 HQWNNYGT   160 HC VariableQVTLKESGPALVKPTQTLTLTCTFSGFSLSTSNMGVVWIRQPPGKALEWLAHILWDDREYSNPALKSRLTISKDTSKNQVVLTMTNMDPVDTATYYCARM SRNYYGSSYVMD YWGQGTLVTVSS   161 LC VariableDIQLTQSPSFLSASVGDRVTITCSASSSVNYMHWYQQKPGKAPKLLIYSTSNLASGVPSRFSGSGSGTEFTLTISSLQPEDFATYY CHQWNNYGTFGQGTKVEIKR   162HCDR1 LYGMN   163 HCDR1 NYGMN   164 HCDR2 WINTYTGEPTYADDFKG   165 HCDR3DTAMDYAMAY   166 HCDR3 DYGKYGDYYAMDY   167 LCDR1 KSSQNIVHSDGNTYLE   168LCDR1 RSSQSIVHSNGNTYLD   169 LCDR2 KVSNRFS   170 LCDR3 FQGSHVPLT   171HC Variable QVQLVQ SGSELKKPGASVKVSCKASGYTFTLYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARDTAMDYAMAYWGQGTLVTVSS   172 HC VariableQVQLVQSGSELKKPGASVKVSCKASGYTFTLYGMNWVKQAPGKGLKWMGWINTYTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARDTAMDYAMAYWGQGTLVTVSS   173 HC VariableQVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMNWVRQAPGQGLEWMGWINTYTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYYCARDYGKYGDYYAMDYWGQGTLVTVSS   174 HC VariableQVQLVQSGSELKKPGASVKVSCKASGYTFTNYGMNWVRQAPGKGLKWMGWINTYTGEPTYADDFKGRFVFSLDTSVSTAYLQISSLKAEDTAVYFCARDYGKYGDYYAMDYWGQGTLVTVSS   175 LC VariableDVVMTQSPLSLPVTLGQPASISCKSSQNIVHSDGNTYLEWFQQRPGQSPRRLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAE DVGVYYCFQGSHVPLTFGGGTKVEIKR  176 LC Variable DVVMTQSPLSLPVTLGQPASISCKSSQNIVHSDGNTYLEWFQQRPGQSPRRLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAE DVGVYYCFQGSHVPLTFGQGTKVEIKR  177 LC Variable DVVMTQTPLSLPVTPGEPASISCKSSQNIVHSDGNTYLEWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAE DLGVYYCFQGSH VPLTFGGGTKVEIKR  178 LC Variable DVVMTQTPLSLPVSLGDQASISCKSSQNIVHSDGNTYLEWYLQKPGQSPKVLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAE DLGVYYCFQGSH VPLTFGGGTKVEIKR  179 LC Variable DVVMTQSPLSLPVTLGQPASISCRSSQSIVHSNGNTYLDWFQQRPGQSPRRLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAE DVGVYYCFQGSH VPLTFGGGTKVEIKR  180 LC Variable DVVMTQSPLSLPVTLGQPASISCRSSQSIVHSNGNTYLDWFQQRPGQSPRRLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAE DVGVYYCFQGSH VPLTFGQGTKVEIKR  181 LC Variable DVVMTQTPLSLPVTPGEPASISCRSSQSIVHSNGNTYLDWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAE DLGVYYCFQGSH VPLTFGGGTKVEIKR  182 LC Variable DVVMTQTPLSLPVSLGDQASISCRSSQSIVHSNGNTYLDWYLQKPGQSPKVLIYKVSNRFSGVPDRFSGSGSGTDFTLKINRVEAE DLGVYFCFQGSH VPLTFGGGTKLEIKR  183 HCDR1 GYTFTSSWMH   184 HCDR2 IHPNSGGT   185 HCDR3 ARGDYYGYVS WFAY  186 LCDR1 QNINVL   187 LCDR2 KAS   188 LCDR3 QQGQSYPYT   189HC Variable QVQLQQPGSV LVRPGASVKV SCKASGYTFT SSWMHWAKQRPGQGLEWIGE IHPNSGGTNY NEKFKGKATV DTSSSTAYVDLSSLTSEDSA VYYCARGDYY GYVSWFAYWG QGTLVTVSS   190 HC VariableQVQLVQSGAE VKKPGASVKV SCKASGYTFT SSWMHWARQAPGQGLEWIGE IHPNSGGTNY AQKFQGRATL TVDTSSSTAYMELSRLRSDD TAVYYCARGD YYGYVSWFAY WGQGTLVTVS S   191 HC VariableQVQLVQSGAE VKKPGASVKV SCKASGYTFT SSWMHWARQAPGQGLEWIGE IHPNSGGTNY AQKFQGRATM TVDTSISTAYMELSRLRSDD TAVYYCARGD YYGYVSWFAY WGQGTLVTVS S   192 HC VariableQVQLVQSGAE VKKPGASVKV SCKASGYTFT SSWMHWARQAPGQGLEWIGE IHPNSGGTNY AQKFQGRVTM TVDTSISTAYMELSRLRSDD TAVYYCARGD YYGYVSWFAY WGQGTLVTVS S   193 HC VariableQVQLVQSGAE VKKPGASVKV SCKASGYTFT SSWMHWARQAPGQGLEWMGE IHPNSGGTNY AQKFQGRVTM TVDTSISTAYMELSRLRSDD TAVYYCARGD YYGYVSWFAY WGQGTLVTVS S   194 LC VariableDIQMNQSPSS LSASLGDTIT ITCHASQNIN VLLSWYQQKPGNIPKLLIYK ASNLHTGVPS RFSGSGSGTG FTFTISSLQPEDIATYYCQQ GQSYPYTFGG GTKLEIK   195 LC VariableDIQMTQSPSS LSASVGDRVT ITCQASQDIS NYLNWYQQKPGKAPKLLIYD ASNLETGVPS RFSGSGSGTD FTFTISSLQPEDIATYYCQQ YDNLPYTFGQ GTKLEIK   196 LC VariableDIQMTQSPSS LSASVGDRVT ITCQASQNIN VLLNWYQQKPGKAPKLLIYK ASNLHTGVPS RFSGSGSGTD FTFTISSLQPEDIATYYCQQ GQSYPYTFGQ GTKLEIK   197 LC VariableDIQMNQSPSS LSASVGDRVT ITCQASQNIN VLLSWYQQKPGKAPKLLIYK ASNLHTGVPS RFSGSGSGTD FTFTISSLQPEDIATYYCQQ GQSYPYTFGQ GTKLEIK   198 HCDR1 GYTFTSYDIN   199 HCDR2WLNPNSGXTG; X = N, Y   200 HCDR3 EVPETAAFEY   201 LCDR1TSSSSDIGA(X1) (X2)GV(X3); X1 = G, A; X2 = L, S, Q; X3 = H, L   202 LCDR2GYYNRPS   203 LCDR3 QSXDGTLSAL; X = Y, W, F   204 HC VariableQVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQAPGQGLEWMGW LNPNSGNTGY AQKFQGRVTM TADRSTSTAYMELSSLRSED TAVYYCAREV PETAAFEYWG QGTLVTVSS   205 LC VariableQSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AXXGVWYQQLPGTAPKLLI EGYYNRPSGV PDRFSGSKSG TSASLTITGLLPEDEGDYYC QSXDGTLSAL FGGGTKLTVL G   206 HC VariableQVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQAPGQGLEWMGW LNPNSGNTGY AQKFQGRVTM TADRSTSTAYMELSSLRSED TAVYYCAREV PETAAFEYWG QGTLVTVSS   207 LC VariableQSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AGLGVHWYQQLPGTAPKLLI EGYYNRPSGV PDRFSGSKSG TSASLTITGLLPEDEGDYYC QSWDGTLSAL FGGGTKLTVL G   208 HC VariableQVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQAPGQGLEWMGW LNPNSGYTGY AQKFQGRVTM TADRSTSTAYMELSSLRSED TAVYYCAREV PETAAFEYWG QGTLVTVSS   209 LC VariableQSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AGLGVHWYQQLPGTAPKLLI EGYYNRPSGV PDRFSGSKSG TSASLTITGLLPEDEGDYYC QSYDGTLSAL FGGGTKLTVL G   210 HC VariableQVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQAPGQGLEWMGW LNPNSGNTGY AQKFQGRVTM TADRSTSTAYMELSSLRSED TAVYYCAREV PETAAFEYWG QGTLVTVSS   211 LC VariableQSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AALGVHWYQQLPGTAPKLLI EGYYNRPSGV PDRFSGSKSG TSASLTITGLLPEDEGDYYC QSWDGTLSAL FGGGTKLTVL G   212 HC VariableQVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQAPGQGLEWMGW LNPNSGNTGY AQKFQGRVTM TADRSTSTAYMELSSLRSED TAVYYCAREV PETAAFEYWG QGTLVTVSS   213 LC VariableQSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AGSGVHWYQQLPGTAPKLLI EGYYNRPSGV PDRFSGSKSG TSASLTITGLLPEDEGDYYC QSWDGTLSAL FGGGTKLTVL G   214 HC VariableQVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQAPGQGLEWMGW LNPNSGNTGY AQKFQGRVTM TADRSTSTAYMELSSLRSED TAVYYCAREV PETAAFEYWG QGTLVTVSS   215 LC VariableQSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AGQGVHWYQQLPGTAPKLLI EGYYNRPSGV PDRFSGSKSG TSASLTITGLLPEDEGDYYC QSWDGTLSAL FGGGTKLTVL G   216 HC VariableQVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQAPGQGLEWMGW LNPNSGNTGY AQKFQGRVTM TADRSTSTAYMELSSLRSED TAVYYCAREV PETAAFEYWG QGTLVTVSS   217 LC VariableQSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AGLGVLWYQQLPGTAPKLLI EGYYNRPSGV PDRFSGSKSG TSASLTITGLLPEDEGDYYC QSWDGTLSAL FGGGTKLTVL G   218 HC VariableQVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQAPGQGLEWMGW LNPNSGYTGY AQKFQGRVTM TADRSTSTAYMELSSLRSED TAVYYCAREV PETAAFEYWG QGTLVTVSS   219 LC VariableQSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AGLGVHWYQQLPGTAPKLLI EGYYNRPSGV PDRFSGSKSG TSASLTITGLLPEDEGDYYC QSWDGTLSAL FGGGTKLTVL G   220 HC VariableQVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQAPGQGLEWMGW LNPNSGYTGY AQKFQGRVTM TADRSTSTAYMELSSLRSED TAVYYCAREV PETAAFEYWG QGTLVTVSS   221 LC VariableQSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AGSGVHWYQQLPGTAPKLLI EGYYNRPSGV PDRFSGSKSG TSASLTITGLLPEDEGDYYC QSWDGTLSAL FGGGTKLTVL G   222 HC VariableQVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQAPGQGLEWMGW LNPNSGYTGY AQKFQGRVTM TADRSTSTAYMELSSLRSED TAVYYCAREV PETAAFEYWG QGTLVTVSS   223 LC VariableQSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AGQGVHWYQQLPGTAPKLLI EGYYNRPSGV PDRFSGSKSG TSASLTITGLLPEDEGDYYC QSWDGTLSAL FGGGTKLTVL G   224 HC VariableQVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQAPGQGLEWMGW LNPNSGYTGY AQKFQGRVTM TADRSTSTAYMELSSLRSED TAVYYCAREV PETAAFEYWG QGTLVTVSS   225 LC VariableQSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AGLGVLWYQQLPGTAPKLLI EGYYNRPSGV PDRFSGSKSG TSASLTITGLLPEDEGDYYC QSWDGTLSAL FGGGTKLTVL G   226 HC VariableQVQLVQSGAE VKKPGASVKV SCKASGYTFT SYDINWVRQAPGQGLEWMGW LNPNSGYTGY AQKFQGRVTM TADRSTSTAYMELSSLRSED TAVYYCAREV PETAAFEYWG QGTLVTVSS   227 LC VariableQSVLTQPPSV SGAPGQRVTI SCTSSSSDIG AGLGVHWYQQLPGTAPKLLI EGYYNRPSGV PDRFSGSKSG TSASLTITGLLPEDEGDYYC QSFDGTLSAL FGGGTKLTVL G   228 HCDR1 SYFWS   229 HCDR2YIYYSGNTKYNPSLKS   230 HCDR3 ETGSYYGFDY   231 LCDR1 RASQSINNYLN   232LCDR2 AASSLQS   233 LCDR3 QQSYSTPRT   234 HC VariableQVQLQESGPGLVKPSETLSLTCTVSGGSISSYFWSWIRQPPGKGLEWIGYIYYSGNTKYNPSLKSRVTISIDTSKNQFSLKLSSVTAADTAVYYCARETGSYYGFDYWGQGTLVTVSS   235 LC VariableDIQMTQSPSSLSASVGDRVTITCRASQSINNYLNWYQQRPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPGDFATY YCQQSYSTPRTFGQGTKLEIK   236HCDR1 GYYWN   237 HCDR2 EINHAGNTNYNPSLKS   238 HCDR3 GYCRSTTCYFDY   239LCDR1 RASQSVRSSYLA   240 LCDR2 GASSRAT   241 LCDR3 QQYGSSPT   242HC Variable QVQLQQWGAGLLKPSETLSLTCAVHGGSFSGYYWNWIRQPPGKGLEWIGEINHAGNTNYNPSLKSRVTISLDTSKNQFSLTLTSVTAADTAVYYCARGYCRSTTCYFDYWGQGTLVTVSS   243 LC VariableEIVLTQSPGTLSLSPGERATLSCRASQSVRSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAV YYCQQYGSSPTFGQGTRLEIK   244HC Variable EVQLQQSGAELVKPGASVKLSCTASGFDIQDTYMHWVKQRPEQGLEWIGRIDPASGHTKYDPKFQVKATITTDTSSNTAYLQLSSLTSEDTAVYYCSRSGGLPDVWGAGTTVTVSS   245 LC VariableQIVLSQSPAILSASPGEKVTMTCRASSSVSYMYWYQQKPGSSPKPWIYATSNLASGVPDRFSGSGSGTSYSLTISRVEAEDAATYY CQQWSGNPRTFGGGTKLEIK   246HCDR1 GFDIQDTYMH   247 HCDR2 RIDPASGHTKYDPKFQV   248 HCDR3 SGGLPDV   249LCDR1 RASSSVSYMY   250 LCDR2 ATSNLAS   251 LCDR3 QQWSGNPRT   252HC Variable QVQLVQSGAEVKKPGASVKLSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIDPASGHTKYDPKFQVRVTMTTDTSTSTVYMELSSLRSEDTAVYYCSRSGGLPDVWGQGTTVTVSS   253 LC VariableEIVLTQSPGTLSLSPGERVTMSCRASSSVSYMYWYQQKPGQAPRPWIYATSNLASGVPDRFSGSGSGTDYTLTISRLEPEDFAVYY CQQWSGNPRTFGGGTKLEIK   254(CDR-grafted QVQLVQSGAEVKKPGASVKLSCKASGFDIQDTYMHWVRQAPGQ LC) HCGLEWMGRIDPASGHTKYDPKFQVRVTMTRDTSTSTVYMELSSL variable regionRSEDTAVYYCSRSGGLPDVWGQGTTVTVSS   255 (CDR-graftedEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAP LC) HCRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY variable regionCQQWSGNPRTFGGGTKLEIK   256 (CDR-graftedQVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQ HC) HCGLEWMGRIDPASGHTKYDPKFQVRVTMTRDTSTSTVYMELSSL variable regionRSEDTAVYYCARSGGLPDVWGQGTTVTVSS   257 (CDR-graftedEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAP HC) LCRLLIYATSNLASGVPDRFSGSGSGTDYTLTISRLEPEDFAVYY variable regionCQQWSGNPRTFGGGTKLEIK   258 HC variableEVMLVESGGGLVKPGGSLKLSCAASGFTFTNYAMSWVRQTPEKRLEWVATITSGGSYIYYLDSVKGRFTISRDNAKSTLYLQMSSLRSEDTAIYNCARRKDGNYYYAMDYWGQGTSVTVSS   259 HC variableEVMLVESGGGLVKPGGSLKLSCAASGFTFTNYAMSWVRQTPEKRLEWVATITSGGSYIYYLDSVKGRFTISRDNAKSTLYLQMSSLRSEDTAIYYCARRKDGNYYYAMDYWGQGTSVTVSS   260 HC variableEVQLVESGGGLVKPGGSLRLSCAASGFTFTNYAMSWVRQAPGQRLEWVSTITSGGSYIYYLDSVKGRFTISRDNAKSTLYLQMNSLRAEDTAVYNCARRKDGNYYYAMDYWGQGTTVTVSS   261 HC variableEVQLVESGGGLVKPGGSLRLSCAASGFTFTNYAMSWVRQAPGQRLEWVSTITSGGSYIYYLDSVKGRFTISRDNAKSTLYLQMNSLRAEDTAVYYCARRKDGNYYYAMDYWGQGTTVTVSS   262 HC variableEVQLLESGGGLVQPGRSLRLSCAASGFTFTNYAMSWVRQAPGQRLEWLATITSGGSYIYYLDSVKGRFTISRDNSKSTLYLQMGSLRAEDMAVYNCARRKDGNYYYAMDYWGQGTTVTVSS   263 HC variableEVQLLESGGGLVQPGRSLRLSCAASGFTFTNYAMSWVRQAPGQRLEWLATITSGGSYIYYLDSVKGRFTISRDNSKSTLYLQMGSLRAEDMAVYYCARRKDGNYYYAMDYWGQGTTVTVSS   264 HC variableQVQLVESGGGLIQPGGSLRLSCAASGFTFTNYAMSWVRQARGQRLEWVSTITSGGSYIYYLDSVKGRFTISRDNSKSTLYMELSSLRSEDTAVYNCARRKDGNYYYAMDYWGQGTTVTVSS   265 HC variableQVQLVESGGGLIQPGGSLRLSCAASGFTFTNYAMSWVRQARGQRLEWVSTITSGGSYIYYLDSVKGRFTISRDNSKSTLYMELSSLRSEDTAVYYCARRKDGNYYYAMDYWGQGTTVTVSS   266 HC variableQVQLVQSGSELKKPGASVKVSCKASGFTFTNYAMSWVRQAPGKRLEWVSTITSGGSYIYYLDSVKGRFTISRENAKSTLYLQMNSLRTEDTALYNCARRKDGNYYYAMDYWGQGTTVTVSS   267 HC variableQVQLVQSGSELKKPGASVKVSCKASGFTFTNYAMSWVRQAPGKRLEWVATITSGGSYIYYLDSVKGRFTISRENAKSTLYLQMNSLRTEDTALYYCARRKDGNYYYAMDYWGQGTTVTVSS   268 HC variableEVQLLQSGAEVKKPGASVKVSCKASGFTFTNYAMSWVRQAPGQRLEWVATITSGGSYIYYLDSVKGRFTISRDNAKSTLHLQMNSLRAEDTAVYNCARRKDGNYYYAMDYWGQGTTVTVSS   269 HC variableEVQLLQSGAEVKKPGASVKVSCKASGFTFTNYAMSWVRQAPGQRLEWVATITSGGSYIYYLDSVKGRFTISRDNAKSTLHLQMNSLRAEDTAIYYCARRKDGNYYYAMDYWGQGTTVTVSS   270 HC variableEVMLLQSGAEVKKPGASVKVSCKASGFTFTNYAMSWVRQAPGQRLEWVATITSGGSYIYYLDSVKGRFTISRDNAKSTLHLQMNSLRAEDTAVYYCARRKDGNYYYAMDYWGQGTTVTVSS   271 LC variableDIVLTQSPASLAVSLGQRATISCRASESVDSYGNSFIHWYQQKAGQPPKLLIYRASNLESGIPARFSGSGSRTDFTLTINPVEADD VATYYCQQSYEDPWTFGGGTKLEIK  272 LC variable DIVLTQSPATLSLSPGERATLSCRASESVDSYGNSFIHWYQQKPGQPPKLLIYRASNLESGIPARFSGSGSRTDFTLTISSLEPED FAVYYCQQSYEDPWTFGGGTKXEIK  273 LC variable DIVLTQSPSSLSASVGDRVTITCRASESVDSYGNSFIHWYQQKPGQPPKLLIYRASNLESGIPARFSGSGSRTDFTLTISSLQPED FATYYCQQSYEDPWTFGGGTKXEIK  274 LC variable DIVLTQSPDFQSVTPKEKVTITCRASESVDSYGNSFIHWYQQKPGQPPKLLIYRASNLESGIPARFSGSGSRTDFTLTISSLEAED AATYYCQQSYEDPWTFGGGTKXEIK  275 LC variable DIVLTQTPLSLSVTPGQPASISCRASESVDSYGNSFIHWYQQKPGQPPKLLIYRASNLESGIPARFSGSGSRTDFTLKISRVEAED VGVYYCQQSYEDPWTFGGGTKXEIK  276 HCDR1 TYGMS   277 HCDR2 WMNTYSGVTTYADDFKG   278 HCDR3EGYVFDDYYATDY   279 LCDR1 RSSQNIVHSDGNTYLE   280 LCDR2 KVSNRFS   281LCDR3 FQGSHVPLT   282 HC VariableQIQLVQSGPELKKPGETVKISCKASGYTFTTYGMSWVKQAPGKGLKWMGWMNTYSGVTTYADDFKGRFAFSLETSASTAYMQIDNLKNEDTATYFCAREGYVFDDYYATDYWGQGTSVTVSS   283 LC VariableDVLMTQTPLSLPVSLGDQASISCRSSQNIVHSDGNTYLEWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAE DLGIYYCFQGSHVPLTFGAGTKLELK  284 HCDR1 KYDIN   285 HCDR2 WIFPGDGRTDYNEKFKG   286 HCDR3 YGPAMDY  287 LCDR1 RSSQTIVHSNGDTYLD   288 LCDR2 KVSNRFS   289 LCDR3 FQGSHVPYT  290 HC Variable MGWSWVFLFLLSVTAGVHSQVHLQQSGPELVKPGASVKLSCKASGYTFTKYDINWVRQRPEQGLEWIGWIFPGDGRTDYNEKFKGKATLTTDKSSSTAYMEVSRLTSEDSAVYFCARYGPAMDYWGQGT SVTVAS   291 LC VariableMKLPVRLLVLMFWIPASSSDVLMTQTPLSLPVSLGDQASISCRSSQTIVHSNGDTYLDWFLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPYTFGGGTKLE IK   484 HCDR1 DTYMEI   485HCDR2 PASGH   486 HCDR3 SGGLPD   487 LCDR1 ASSSVSYMY   488 LCDR2 ATSNLAS  489 LCDR3 GNPRT   490 VL EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWSGNPRTFGGGTKLEIK   491VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIDPASGHTKYDPKFQVRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGLPDVWGQGTTVTVSS   492 VLEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWEGNPRTFGGGTKLEIK   493VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIEPASGHIKYDPKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGLPDWWGQGTTVTVSS   494 VLEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWEGNPRTFGGGTKLEIK   495VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIEPASGHIKYSPKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGLPDWWGQGTTVTVSS   496 VLEIVLTQSPGTLSLSPGERATLSCGASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWEGNPRTFGGGTKLEIK   497VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIEPASGHIKYSPKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGLPDWWGQGTTVTVSS   498 VLEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWEGNPRTFGGGTKLEIK   499VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIEPASGHVKYSPKFQVRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGLPDWWGQGTTVTVSS   500 VLEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWEGNPRTFGGGTKLEIK   501VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIEPASGHVKYDPKFQTRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGLPDWWGQGTTVTVSS   502 VLEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWQGNPRTFGGGTKLEIK   503VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIDPASGHiKYDPKFQkRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGLPDMWGQGTTVTVSS   504 VLEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWQGNPRTFGGGTKLEIK   505VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIDPASGHvKiDPKFQVRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGLPDMWGQGTTVTVSS   506 VLEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWQGNPRTFGGGTKLEIK   507VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIDPASGHLKYDPKFQVRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGLPDMWGQGTTVTVSS   508 VLEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWQGNPRTFGGGTKLEIK   509VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIDPASGHLKYDPKFQRRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGLPDMWGQGTTVTVSS   510 VLEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWEGNPRTFGGGTKLEIK   511VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIDPASGHLKYDPKFQNRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGLPDKWGQGTTVTVSS   512 VLEIVLTQSPGTLSLSPGERATLSCGASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWEGNPRTFGGGTKLEIK   513VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIDPASGHLKYDPKFQNRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGLPDKWGQGTTVTVSS   514 VLEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWEGNPRTFGGGTKLEIK   515VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIEPASGHLKYDPKFQERVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGLPDKWGQGTTVTVSS   516 VLEIVLTQSPGTLSLSPGERATLSCGASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWEGNPRTFGGGTKLEIK   517VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIEPASGHLKYDPKFQERVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGLPDKWGQGTTVTVSS   518 VLEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWQGNPRTFGGGTKLEIK   519VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIDPASGHLKYDPKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCARSGGLPDMWGQGTTVTVSS   520 VLEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWQGNPRTFGGGTKLEIK   521VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQQGLEWMGRIDPASGHLKYDPKFQGRVTITRDTSASTVYNIELSSLRSEDTAVYYCARSGGLPDMWGQGTTVTVSS   522 VLEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWSGNPRTFGGGTKLEIK   523VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIDPASGHTKYDPKFQGRATITTDTSASTAYLQLSSLRSEDTAVYYCARSGGLPDVWGQGTTVTVSS   524 VLEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWSGNPRTFGGGTKLEIK   525VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIDPASGHTKYDPKFQVRATITTDTSASTAYLQLSSLRSEDTAVYYCARSGGLPDFWGQGTTVTVSS   526 VLEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWSGNPRTFGGGTKLEIK   527VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIDPASGHTKYDPKFQGRATITTDTSASTAYLQLSSLRSEDTAVYYCARSGGLPDFWGQGTTVTVSS   528 VLEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWSGNPRTFGGGTKLEIK   529VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIDPASGHTKYDPKFQGRATITTDTSASTAYLQLSSLRSEDTAVYYCARSGGLPDLWGQGTTVTVSS   530 VLEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CSQWSGNPRTFGGGTKLEIK   531VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIDPASGHTKYDPKFQGRATITTDTSASTAYLQLSSLRSEDTAVYYCARSGGLPDFWGQGTTVTVSS   532 VLEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWSGNPRSFGGGTKLEIK   533VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIDPASGHTKYDPKFQGRATITTDTSASTAYLQLSSLRSEDTAVYYCARSGGLPDFWGQGTTVTVSS   534 VLEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWSRNPRTFGGGTKLEIK   535VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIDPASGHTKYDPKFQGRATITTDTSASTAYLQLSSLRSEDTAVYYCARSGGLPDFWGQGTTVTVSS   536 VLEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWKGNPRTFGGGTKLEIK   537VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIDPASGHTKYDPKFQGRATITTDTSASTAYLQLSSLRSEDTAVYYCARSGGLPDFWGQGTTVTVSS   538 VLEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWSGNPRTFGGGTKLEIK   539VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIDPASGHSKYDPKFQVRATITTDTSASTAYLQLSSLRSEDTAVYYCARSGGLPDFWGQGTTVTVSS   540 VLEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWSGNPRTFGGGTKLEIK   541VH QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIDPASGHYKYDPKFQVRATITTDTSASTAYLQLSSLRSEDTAVYYCARSGGLPDFWGQGTTVTVSS   542 ModifiedASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNS IgG1-ConstantGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN regionHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGAPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK   543 IgG2 constantASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNS regionGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNV FSCSVMHEALHNHYTQKSLSLSPGK  544 Kappa constant RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKV regionDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYA CEVTHQGLSSPVTKSFNRGEC   545HFR1 QVQLVQSGAEVKKPGASVKVSCKAS   546 HFR2 WVRQAPGQGLEWMG   547 HFR3RVTMTRDTSTSTVYMELSSLRSEDTAVYYC   548 HFR4 WGQGTTVTVSS   549 LFR1EIVLTQSPGTLSLSPGERATLSC   550 LFR2 WYQQKPGQAPRLLIY   551 LFR3GIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC   552 LFR4 FGGGTKLEIK   553 HCDR1GFDIQDTYMH   554 HCDR2 RIDPASGHTKYDPKFQV   555 HCDR2 RIEPASGHIKYDPKFQG  556 HCDR2 RIEPASGHIKYSPKFQG   557 HCDR2 RIEPASGHVKYSPKFQV   558 HCDR2RIEPASGHVKYDPKFQT   559 HCDR2 RIDPASGHIKYDPKFQK   560 HCDR2RIDPASGHVKIDPKFQV   561 HCDR2 RIDPASGHLKYDPKFQV   562 HCDR2RIDPASGHLKYDPKFQR   563 HCDR2 RIDPASGHLKYDPKFQN   564 HCDR2RIEPASGHLKYDPKFQE   565 HCDR3 ARSGGLPDV   566 HCDR3 ARSGGLPDW   567HCDR3 ARSGGLPDM   568 HCDR3 ARSGGLPDK   569 LCDR1 RASSSVSYMY   570 LCDR1GASSSVSYMY   571 LCDR3 QQWSGNPRT   572 LCDR3 QQWEGNPRT   573 LCDR3QQWQGNPRT   574 HCDR2 RIDPASGHLKYDPKFQG   575 HCDR2 RIDPASGHTKYDPKFQG  576 HCDR2 RIDPASGHSKYDPKFQV   577 HCDR2 RIDPASGHYKYDPKFQV   578 HCDR3ARSGGLPDV   579 HCDR3 ARSGGLPDM   580 HCDR3 ARSGGLPDF   581 HCDR3ARSGGLPDL   582 LCDR3 SQWSGNPRT   583 LCDR3 QQWSGNPRS   584 LCDR3QQWSRNPRT   585 LCDR3 QQWKGNPRT   586 HFR3RATITTDTSASTAYLQLSSLRSEDTAVYYC   587 HFR3 RVTITRDTSASTVYMELSSLRSEDTAVYYC  588 HFR3 RVTITRDTSASTAYMELSSLRSEDTAVYYC  1001 HC VariableGAAGTTCAGCTGCAACAGTCTGGCGCCGAGCTGGTTAAGCCTGGCGCTTCTGTGAAGCTGAGCTGTACCGCCTCTGGCTTCGACATCCAAGACACCTACATGCACTGGGTCAAGCAGAGGCCTGAGCAGGGACTCGAGTGGATCGGCAGAATTGATCCTGCCAGCGGCCACACCAAATACGACCCCAAGTTCCAAGTGAAGGCCACCATCACCACCGACACCAGCAGCAATACCGCCTACCTGCAGCTGAGCAGCCTGACCTCTGAAGATACCGCCGTGTACTACTGCAGCAGATCTGGCGGACTGCCCGATGTTTGGGGAGCCGGAACAACCGTGACAGTGTC CAGC  1002 HC VariableGAGGTTCAACTTCAACAATCGGGGGCCGAGCTGGTTAAGCCCGGCGCTTCTGTAAAATTGTCTTGCACTGCCTCTGGGTTTGACATCCAAGATACATATATGCATTGGGTGAAACAGCGTCCCGAGCAGGGCTTGGAGTGGATTGGACGTATTGACCCCGCCTCTGGGCACACGAAATATGATCCTAAGTTCCAGGTTAAAGCGACTATCACAACGGACACCTCCAGCAATACGGCTTATTTACAGTTATCCTCGCTGACCTCTGAGGATACTGCAGTGTACTACTGCTCTCGCTCTGGTGGTCTGCCAGACGTGTGGGGTGCAGGAACTACAGTTACTGTGTC TTCA  1003 HC VariableEVQLQQSGAELVKPGASVKLSCTASGFDIQDTYMHWVKQRPEQGLEWIGRIDPASGHTKYDPKFQVKATITTDTSSNTAYLQLSSLTSEDTAVYYCSRSGGLPDVWGAGTTVTVSS  1004 LC VariableCAAATTGTGCTGTCTCAGAGCCCCGCCATCCTGAGTGCTTCTCCAGGCGAGAAAGTGACCATGACCTGCAGAGCCAGCAGCAGCGTGTCCTACATGTACTGGTATCAGCAGAAGCCCGGCAGCAGCCCCAAGCCTTGGATCTACGCCACAAGCAATCTGGCCAGCGGCGTGCCCGATAGATTTTCTGGCTCTGGCAGCGGCACCAGCTACAGCCTGACAATCTCTAGAGTGGAAGCCGAGGATGCCGCCACCTACTACTGTCAACAGTGGAGCGGCAACCCCAGAACCTTTGGC GGAGGCACCAAGCTGGAAATCAAG 1005 LC Variable CAAATCGTCCTGTCACAGTCCCCGGCGATCCTTTCTGCTTCACCAGGAGAGAAGGTAACCATGACATGTCGCGCCTCTTCCTCAGTTTCTTACATGTACTGGTACCAGCAGAAACCAGGATCATCTCCCAAACCCTGGATCTACGCTACATCAAACCTTGCATCTGGCGTGCCAGACCGTTTTTCAGGGTCGGGCTCGGGGACTTCCTATTCATTAACCATTTCTCGCGTAGAAGCGGAAGACGCCGCCACGTATTATTGTCAGCAGTGGTCAGGAAATCCGCGCACATTCGGA GGCGGAACGAAATTGGAGATCAAA 1006 LC Variable QIVLSQSPAILSASPGEKVTMTCRASSSVSYMYWYQQKPGSSPKPWIYATSNLASGVPDRFSGSGSGTSYSLTISRVEAEDAAT YYCQQWSGNPRTFGGGTKLEIK  1007HCDR1 GGCTTCGACATCCAAGACACCTACATGCAC  1008 HCDR1GGGTTTGACATCCAAGATACATATATGCAT  1009 HCDR1 GFDIQDTYMH 10010 HCDR2AGAATTGATCCTGCCAGCGGCCACACCAAATACGACCCCAAGT TCCAAGTG 10011 HCDR2CGTATTGACCCCGCCTCTGGGCACACGAAATATGATCCTAAGT TCCAGGTT 10012 HCDR2RIDPASGHTKYDPKFQV 10013 HCDR3 TCTGGCGGACTGCCCGATGTT 10014 HCDR3TCTGGTGGTCTGCCAGACGTG 10015 HCDR3 SGGLPDV 10016 LCDR1AGAGCCAGCAGCAGCGTGTCCTACATGTAC 10017 LCDR1CGCGCCTCTTCCTCAGTTTCTTACATGTAC 10018 LCDR1 RASSSVSYMY 10019 LCDR2GCCACAAGCAATCTGGCCAGC 10020 LCDR2 GCTACATCAAACCTTGCATCT 10021 LCDR2ATSNLAS 10022 LCDR3 CAACAGTGGAGCGGCAACCCCAGAACC 10023 LCDR3CAGCAGTGGTCAGGAAATCCGCGCACA 10024 LCDR3 QQWSGNPRT 10025 HC VariableCAAGTACAATTAGTCCAGTCGGGTGCCGAGGTAAAAAAACCTGGAGCATCCGTAAAACTGTCTTGCAAAGCATCGGGGTTTGACATCCAGGACACCTACATGCACTGGGTGCGTCAAGCTCCAGGACAGGGATTAGAGTGGATGGGTCGCATCGACCCCGCGAGCGGACACACGAAATACGACCCTAAATTTCAAGTACGTGTCACGATGACTACCGACACTAGTACGAGCACTGTTTATATGGAATTGTCCTCGTTACGCTCAGAGGATACGGCAGTCTATTATTGCAGCCGTTCCGGAGGCTTACCCGACGTCTGGGGACAGGGAACTACTGTAACAGTCAG TAGT 10026 HC VariableQVQLVQSGAEVKKPGASVKLSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIDPASGHTKYDPKFQVRVTMTTDTSTSTVYMELSSLRSEDTAVYYCSRSGGLPDVWGQGTTVTVSS 10027 LC VariableGAGATTGTGTTAACGCAATCACCGGGGACTTTATCGCTGTCGCCGGGGGAGCGCGTTACAATGTCTTGTCGCGCTTCCTCTTCGGTTTCATACATGTATTGGTATCAACAAAAACCGGGACAGGCTCCACGCCCCTGGATTTACGCTACTAGCAATTTGGCCTCGGGCGTTCCCGACCGCTTCAGCGGGTCAGGGAGCGGCACCGATTACACGTTGACCATCTCTCGTCTGGAACCTGAAGACTTCGCGGTCTATTACTGTCAACAATGGTCGGGAAATCCCCGTACATTTGGCGGAGGGA CGAAGTTGGAAATTAAA 10028LC Variable EIVLTQSPGTLSLSPGERVTMSCRASSSVSYMYWYQQKPGQAPRPWIYATSNLASGVPDRFSGSGSGTDYTLTISRLEPEDFAVYY CQQWSGNPRTFGGGTKLEIK 10029HCDR1 GGGTTTGACATCCAGGACACCTACATGCAC 10030 HCDR2CGCATCGACCCCGCGAGCGGACACACGAAATACGACCCTAAAT TTCAAGTA 10031 HCDR3TCCGGAGGCTTACCCGACGTC 10032 LCDR1 CGCGCTTCCTCTTCGGTTTCATACATGTATTGGTAT10033 LCDR2 GCTACTAGCAATTTGGCCTCG 10034 LCDR3CAACAATGGTCGGGAAATCCCCGTACA 10035 LC VariableCAAGTACAATTAGTCCAGTCGGGTGCCGAGGTAAAAAAACCTGGAGCATCCGTAAAACTGTCTTGCAAAGCATCGGGGTTTGACATCCAGGACACCTACATGCACTGGGTGCGTCAAGCTCCAGGACAGGGATTAGAGTGGATGGGTCGCATCGACCCCGCGAGCGGACACACGAAATACGACCCTAAATTTCAAGTACGTGTCACGATGACTCGTGACACTAGTACGAGCACTGTTTATATGGAATTGTCCTCGTTACGCTCAGAGGATACGGCAGTCTATTATTGCAGCCGTTCCGGAGGCTTACCCGACGTCTGGGGACAGGGAACTACTGTAACAGTCAG TAGT 10036 LC VariableQVQLVQSGAEVKKPGASVKLSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIDPASGHTKYDPKFQVRVTMTRDTSTSTVYMELSSLRSEDTAVYYCSRSGGLPDVWGQGTTVTVSS 10037 LC VariableGAGATTGTGTTAACGCAATCACCGGGGACTTTATCGCTGTCGCCGGGGGAGCGCGCGACACTGTCTTGTCGCGCTTCCTCTTCGGTTTCATACATGTATTGGTATCAACAAAAACCGGGACAGGCTCCACGCCTGCTGATTTACGCTACTAGCAATTTGGCCTCGGGCATCCCCGACCGCTTCAGCGGGTCAGGGAGCGGCACCGATTTTACGTTGACCATCTCTCGTCTGGAACCTGAAGACTTCGCGGTCTATTACTGTCAACAATGGTCGGGAAATCCCCGTACATTTGGCGGAGGGA CGAAGTTGGAAATTAAA 10038LC Variable EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWSGNPRTFGGGTKLEIK 10039HC Variable CAAGTACAATTAGTCCAGTCGGGTGCCGAGGTAAAAAAACCTGGAGCATCCGTAAAAGTCTCTTGCAAAGCATCGGGGTTTGACATCCAGGACACCTACATGCACTGGGTGCGTCAAGCTCCAGGACAGGGATTAGAGTGGATGGGTCGCATCGACCCCGCGAGCGGACACACGAAATACGACCCTAAATTTCAAGTACGTGTCACGATGACTCGTGACACTAGTACGAGCACTGTTTATATGGAATTGTCCTCGTTACGCTCAGAGGATACGGCAGTCTATTATTGCGCACGTTCCGGAGGCTTACCCGACGTCTGGGGACAGGGAACTACTGTAACAGTCAG TAGT 10040 HC VariableQVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMEIWVRQAPGQGLEWMGRIDPASGHTKYDPKFQVRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGLPDVWGQGTTVTVSS 10041 HC VariableGAGATTGTGTTAACGCAATCACCGGGGACTTTATCGCTGTCGCCGGGGGAGCGCGCGACACTGTCTTGTCGCGCTTCCTCTTCGGTTTCATACATGTATTGGTATCAACAAAAACCGGGACAGGCTCCACGCCTGCTGATTTACGCTACTAGCAATTTGGCCTCGGGCGTTCCCGACCGCTTCAGCGGGTCAGGGAGCGGCACCGATTACACGTTGACCATCTCTCGTCTGGAACCTGAAGACTTCGCGGTCTATTACTGTCAACAATGGTCGGGAAATCCCCGTACATTTGGCGGAGGGA CGAAGTTGGAAATTAAA 10042HC Variable EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGVPDRFSGSGSGTDYTLTISRLEPEDFAVYY CQQWSGNPRTFGGGTKLEIK 10043HC Variable QVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMEIWVRQAPGQGLEWMGRIDPASGHTKYDPKFQVRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGLPDKWGQGTTVTVSS 10044 HC VariableQVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMEIWVRQAPGQGLEWMGRIDPASGHTKYDPKFQVRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGLPDMWGQGTTVTVSS 10045 HC VariableQVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMEIWVRQAPGQGLEWMGRIDPASGHTKYDPKFQVRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGLPDQWGQGTTVTVSS 10046 HC VariableQVQLVQSGAEVKKPGASVKVSCKASGFDIQDTYMHWVRQAPGQGLEWMGRIDPASGHTKYDPKFQVRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGLPDWWGQGTTVTVSS 10047 LC VariableEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWDGNPRTFGGGTKLEIK 10048LC Variable EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWEGNPRTFGGGTKLEIK 10049LC Variable EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWHGNPRTFGGGTKLEIK 10050LC Variable EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWNGNPRTFGGGTKLEIK 10051LC Variable EIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CQQWQGNPRTFGGGTKLEIK 10052HC Variable QVQLVQSGAEVKKPGASVKVSCKASGFX₁X₂X₃DTX₄X₅HWVRQAPGQGLEWMGRIDPASGHTKYDPKFQVRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSGGX₆PDX₇WGQGTTVTVSS X₁ = D, OR E X₂ = I, P, OR VX₃ = G, Q, S, OR V X₄ = F, OR Y X₅ = I, OR M X₆ = L, OR MX₇ = E, I, K, L, M, Q, T, V, W, OR Y 10053 LC VariableEIVLTQSPGTLSLSPGERATLSCRASSSVSYMYWYQQKPGQAPRLLIYATSNLASGIPDRFSGSGSGTDFTLTISRLEPEDFAVYY CX₁QWX₂X₃X₄PRTFGGGTKLEIKX₁ = Q, OR N X₂ = D, E, H, N, Q, OR S X₃ = A, OR GX₄ = D, F, K, N, R, S, OR T 10054 HC VariableQVQLVQSGAEVKKPGASVKVSCKASGFX₁X₂X₃DTX₄X₅HWVRQAPGQGLEWMGRIDPASGHTKYDPKFQVRVTMTRDTSTSTVYMELSSLRSEDTAVYYCSRSGGX₆PDX₇WGQGTTVTVSS X₁ = D, OR E X₂ = I, P, OR VX₃ = G, Q, S, OR V X₄ = F, OR Y X₅ = I, OR M X₆ = L, OR MX₇ = E, I, K, L, M, Q, T, V, W, OR Y 100100 HCFR1aQVQLVQSGAEVKKPGASVKLSCKAS 100101 HCFR2a WVRQAPGQGLEWMG 100102 HCFR3aRVTMTRDTSTSTVYMELSSLRSEDTAVYYCSR 100103 HCFR4a WGQGTTVTVSS 100104 LCFR1aEIVLTQSPGTLSLSPGERATLSC 100105 LCFR2a WYQQKPGQAPRLLIY 100106 LCFR3aGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYC 100107 LCFR4a FGGGTKLEIK 100108 HCFR1bQVQLVQSGAEVKKPGASVKVSCKAS 100109 HCFR3b RVTMTRDTSTSTVYMELSSLRSEDTAVYYCAR100110 LCFR3b GVPDRFSGSGSGTDYTLTISRLEPEDFAVYYC 100150 HCDR1AGFX₁X₂X₃DTX₄X₅H X₁ = D, OR E X₂ = I, P, OR V X₃ = G, Q, S, OR VX₄ = F, OR Y X₅ = I, OR M 100152 HCDR3 A SGGX₁PDX₂ X₁ = L, OR MX₂ = E, I, K, L, M, Q, T, V, W, OR Y 100155 LCDR3 A X₁QWX₂X₃X₄PRTX₁ = Q, OR N X₂ = D, E, H, N, Q, OR S X₃ = A, OR GX₄ = D, F, K, N, R, S, OR T 100200 HCDR1 A1 GFDIGDTFIH 100201 HCDR1 B1GFDIGDTFMH 100202 HCDR1 C1 GFDIGDTYIH 100203 HCDR1 D1 GFDIGDTYMH 100204HCDR1 E1 GFDIQDTFIH 100205 HCDR1 F1 GFDIQDTFMH 100206 HCDR1 G1GFDIQDTYIH 100207 HCDR1 H1 GFDIQDTYMH 100208 HCDR1 I1 GFDISDTFIH 100209HCDR1 J1 GFDISDTFMH 100210 HCDR1 K1 GFDISDTYIH 100211 HCDR1 L1GFDISDTYMH 100212 HCDR1 M1 GFDIVDTFIH 100213 HCDR1 N1 GFDIVDTFMH 100214HCDR1 O1 GFDIVDTYIH 100215 HCDR1 P1 GFDIVDTYMH 100216 HCDR1 Q1GFDPGDTFIH 100217 HCDR1 R1 GFDPGDTFMH 100218 HCDR1 S1 GFDPGDTYIH 100219HCDR1 T1 GFDPGDTYMH 100220 HCDR1 U1 GFDPQDTFIH 100221 HCDR1 V1GFDPQDTFMH 100222 HCDR1 W1 GFDPQDTYIH 100223 HCDR1 X1 GFDPQDTYMH 100224HCDR1 Y1 GFDPSDTFIH 100225 HCDR1 Z1 GFDPSDTFMH 100226 HCDR1 A2GFDPSDTYIH 100227 HCDR1 B2 GFDPSDTYMH 100228 HCDR1 C2 GFDPVDTFIH 100229HCDR1 D2 GFDPVDTFMH 100230 HCDR1 E2 GFDPVDTYIH 100231 HCDR1 F2GFDPVDTYMH 100232 HCDR1 G2 GFDVGDTFIH 100233 HCDR1 H2 GFDVGDTFMH 100234HCDR1 I2 GEDVGDTY1H 100235 HCDR1 J2 GFDVGDTYMH 100236 HCDR1 K2GFDVQDTFIH 100237 HCDR1 L2 GFDVQDTFMH 100238 HCDR1 M2 GFDVQDTYIH 100239HCDR1 N2 GFDVQDTYMH 100240 HCDR1 02 GFDVSDTFIH 100241 HCDR1 P2GFDVSDTFMH 100242 HCDR1 Q2 GFDVSDTYIH 100243 HCDR1 R2 GFDVSDTYMH 100244HCDR1 S2 GFDVVDTFIH 100245 HCDR1 T2 GFDVVDTFMH 100246 HCDR1 U2GFDVVDTYIH 100247 HCDR1 V2 GFDVVDTYMH 100248 HCDR1 W2 GFEIGDTFIH 100249HCDR1 X2 GFEIGDTFMH 100250 HCDR1 Y2 GFEIGDTYIH 100251 HCDR1 Z2GFEIGDTYMH 100252 HCDR1 A3 GFEIQDTFIH 100253 HCDR1 B3 GFEIQDTFMH 100254HCDR1 C3 GFEIQDTYIH 100255 HCDR1 D3 GFEIQDTYMH 100256 HCDR1 E3GFEISDTFIH 100257 HCDR1 F3 GFEISDTFMH 100258 HCDR1 G3 GFEISDTYIH 100259HCDR1 H3 GFEISDTYMH 100260 HCDR1 I3 GFEIVDTFIH 100261 HCDR1 J3GFEIVDTFMH 100262 HCDR1 K3 GFEIVDTYIH 100263 HCDR1 L3 GFEIVDTYMH 100264HCDR1 M3 GFEPGDTFIH 100265 HCDR1 N3 GFEPGDTFMH 100266 HCDR1 03GFEPGDTYIH 100267 HCDR1 P3 GFEPGDTYMH 100268 HCDR1 Q3 GFEPQDTFIH 100269HCDR1 R3 GFEPQDTFMH 100270 HCDR1 S3 GFEPQDTYIH 100271 HCDR1 T3GFEPQDTYMH 100272 HCDR1 U3 GFEPSDTFIH 100273 HCDR1 V3 GFEPSDTFMH 100274HCDR1 W3 GFEPSDTYIH 100275 HCDR1 X3 GFEPSDTYMH 100276 HCDR1 Y3GFEPVDTFIH 100277 HCDR1 Z3 GFEPVDTFMH 100278 HCDR1 A4 GFEPVDTYIH 100279HCDR1 B4 GFEPVDTYMH 100280 HCDR1 C4 GFEVGDTFIH 100281 HCDR1 D4GFEVGDTFMH 100282 HCDR1 E4 GFEVGDTYIH 100283 HCDR1 F4 GFEVGDTYMH 100284HCDR1 G4 GFEVQDTFIH 100285 HCDR1 H4 GFEVQDTFMH 100286 HCDR1 I4GFEVQDTYIH 100287 HCDR1 J4 GFEVQDTYMH 100288 HCDR1 K4 GFEVSDTFIH 100289HCDR1 L4 GFEVSDTFMH 100290 HCDR1 M4 GFEVSDTYIH 100291 HCDR1 N4GFEVSDTYMH 100292 HCDR1 O4 GFEVVDTFIH 100293 HCDR1 P4 GFEVVDTFMEI 100294HCDR1 Q4 GFEVVDTYIH 100295 HCDR1 R4 GFEVVDTYMEI 100296 HCDR3 A1 SGGLPDE100297 HCDR3 B1 SGGLPDI 100298 HCDR3 C1 SGGLPDK 100299 HCDR3 D1 SGGLPDL100300 HCDR3 E1 SGGLPDM 100301 HCDR3 F1 SGGLPDQ 100302 HCDR3 G1 SGGLPDT100303 HCDR3 H1 SGGLPDW 100304 HCDR3 I1 SGGLPDY 100305 HCDR3 J1 SGGMPDE100306 HCDR3 K1 SGGMPDI 100307 HCDR3 L1 SGGMPDK 100308 HCDR3 M1 SGGMPDL100309 HCDR3 N1 SGGMPDM 100310 HCDR3 O1 SGGMPDQ 100311 HCDR3 P1 SGGMPDT100312 HCDR3 Q1 SGGMPDV 100313 HCDR3 R1 SGGMPDW 100314 HCDR3 S1 SGGMPDY100315 LCDR3 A1 QQWDADPRT 100316 LCDR3 B1 QQWDAFPRT 100317 LCDR3C1QQWDAKPRT 100318 LCDR3 D1 QQWDANPRT 100319 LCDR3 E1 QQWDARPRT 100320LCDR3 F1 QQWDASPRT 100321 LCDR3 G1 QQWDATPRT 100322 LCDR3 H1 QQWDGDPRT100323 LCDR3 I1 QQWDGFPRT 100324 LCDR3 J1 QQWDGKPRT 100325 LCDR3 K1QQWDGNPRT 100326 LCDR3 L1 QQWDGRPRT 100327 LCDR3 M1 QQWDGSPRT 100328LCDR3 N1 QQWDGTPRT 100329 LCDR3 O1 QQWEADPRT 100330 LCDR3 P1 QQWEAFPRT100331 LCDR3 Q1 QQWEAKPRT 100332 LCDR3 R1 QQWEANPRT 100333 LCDR3 S1QQWEARPRT 100334 LCDR3 T1 QQWEASPRT 100335 LCDR3 U1 QQWEATPRT 100336LCDR3 V1 QQWEGDPRT 100337 LCDR3 W1 QQWEGFPRT 100338 LCDR3 X1 QQWEGKPRT100339 LCDR3 Y1 QQWEGNPRT 100340 LCDR3 Z1 QQWEGRPRT 100341 LCDR3 A2QQWEGSPRT 100342 LCDR3 B2 QQWEGTPRT 100343 LCDR3 C2 QQWHADPRT 100344LCDR3 D2 QQWHAFPRT 100345 LCDR3 E2 QQWHAKPRT 100346 LCDR3 F2 QQWHANPRT100347 LCDR3 G2 QQWHARPRT 100348 LCDR3 H2 QQWHASPRT 100349 LCDR3 I2QQWHATPRT 100350 LCDR3 J2 QQWHGDPRT 100351 LCDR3 K2 QQWHGFPRT 100352LCDR3 L2 QQWHGKPRT 100353 LCDR3 M2 QQWHGNPRT 100354 LCDR3 N2 QQWHGRPRT100355 LCDR3 O2 QQWHGSPRT 100356 LCDR3 P2 QQWHGTPRT 100357 LCDR3 Q2QQWNADPRT 100358 LCDR3 R2 QQWNAFPRT 100359 LCDR3 S2 QQWNAKPRT 100360LCDR3 T2 QQWNANPRT 100361 LCDR3 U2 QQWNARPRT 100362 LCDR3 V2 QQWNASPRT100363 LCDR3 W2 QQWNATPRT 364100 LCDR3 X2 QQWNGDPRT 100365 LCDR3 Y2QQWNGFPRT 100366 LCDR3 Z2 QQWNGKPRT 100367 LCDR3 A3 QQWNGNPRT 100368LCDR3 B3 QQWNGRPRT 100369 LCDR3 C3 QQWNGSPRT 100370 LCDR3 D3 QQWNGTPRT100371 LCDR3 E3 QQWQADPRT 100372 LCDR3 F3 QQWQAFPRT 100373 LCDR3 G3QQWQAKPRT 100374 LCDR3 H3 QQWQANPRT 100375 LCDR3 I3 QQWQARPRT 100376LCDR3 J3 QQWQASPRT 100377 LCDR3 K3 QQWQATPRT 100378 LCDR3 L3 QQWQGDPRT100379 LCDR3 M3 QQWQGFPRT 100380 LCDR3 N3 QQWQGKPRT 100381 LCDR3 O3QQWQGNPRT 100382 LCDR3 P3 QQWQGRPRT 100383 LCDR3 Q3 QQWQGSPRT 100384LCDR3 R3 QQWQGTPRT 100385 LCDR3 S3 QQWSADPRT 100386 LCDR3 T3 QQWSAFPRT100387 LCDR3 U3 QQWSAKPRT 100388 LCDR3 V3 QQWSANPRT 100389 LCDR3 W3QQWSARPRT 100390 LCDR3 X3 QQWSASPRT 100391 LCDR3 Y3 QQWSATPRT 100392LCDR3 Z3 QQWSGDPRT 100393 LCDR3 A4 QQWSGFPRT 100394 LCDR3 B4 QQWSGKPRT100395 LCDR3 C4 QQWSGNPRT 100396 LCDR3 D4 QQWSGRPRT 100397 LCDR3 E4QQWSGSPRT 100398 LCDR3 F4 QQWSGTPRT 100399 LCDR3 G4 QQWDADPRT 100400LCDR3 H4 NQWDAFPRT 100401 LCDR3 I4 NQWDAKPRT 100402 LCDR3 J4 NQWDANPRT100403 LCDR3 K4 NQWDARPRT 100404 LCDR3 L4 NQWDASPRT 100405 LCDR3 M4NQWDATPRT 100406 LCDR3 N4 NQWDGDPRT 100407 LCDR3 O4 NQWDGFPRT 100408LCDR3 P4 NQWDGKPRT 100409 LCDR3 Q4 NQWDGNPRT 100410 LCDR3 R4 NQWDGRPRT100411 LCDR3 S4 NQWDGSPRT 100412 LCDR3 T4 NQWDGTPRT 100413 LCDR3 U4NQWEADPRT 100414 LCDR3 V4 NQWEAFPRT 100415 LCDR3 W4 NOWEAKPRT 100416LCDR3 X4 NQWEANPRT 100417 LCDR3 Y4 NQWEARPRT 100418 LCDR3 Z4 NQWEASPRT100419 LCDR3 A5 NQWEATPRT 100420 LCDR3 B5 NQWEGDPRT 100421 LCDR3 C5NQWEGFPRT 100422 LCDR3 D5 NQWEGKPRT 100423 LCDR3 E5 NQWEGNPRT 100424LCDR3 F5 NQWEGRPRT 100425 LCDR3 G5 NQWEGSPRT 100426 LCDR3 H5 NQWEGTPRT100427 LCDR3 I5 NQWHADPRT 100428 LCDR3 J5 NQWHAFPRT 100429 LCDR3 K5NQWHAKPRT 100430 LCDR3 L5 NQWHANPRT 100431 LCDR3 M5 NQWHARPRT 100432LCDR3 N5 NQWHASPRT 100433 LCDR3 O5 NQWHATPRT 100434 LCDR3 PS NQWHGDPRT100435 LCDR3 Q5 NQWHGFPRT 100436 LCDR3 R5 NQWHGKPRT 100437 LCDR3 S5NQWHGNPRT 100438 LCDR3 T5 NQWHGRPRT 100439 LCDR3 U5 NQWHGSPRT 100440LCDR3 V5 NQWHGTPRT 100441 LCDR3 W5 NQWNADPRT 100442 LCDR3 X5 NQWNAFPRT100443 LCDR3 Y5 NQWNAKPRT 100444 LCDR3 Z5 NQWNANPRT 100445 LCDR3 A6NQWNARPRT 100446 LCDR3 B6 NQWNASPRT 100447 LCDR3 C6 NQWNATPRT 100448LCDR3 D6 NQWNGDPRT 100449 LCDR3 E6 NQWNGFPRT 100450 LCDR3 F6 NQWNGKPRT100451 LCDR3 G6 NQWNGNPRT 100452 LCDR3 H6 NQWNGRPRT 100453 LCDR3 I6NQWNGSPRT 100454 LCDR3 J6 NQWNGTPRT 100455 LCDR3 K6 NQWQADPRT 100456LCDR3 L6 NQWQAFPRT 100457 LCDR3 M6 NQWQAKPRT 100458 LCDR3 N6 NQWQANPRT100459 LCDR3 O6 NQWQARPRT 100460 LCDR3 P6 NQWQASPRT 100461 LCDR3 Q6NQWQATPRT 100462 LCDR3 R6 NQWQGDPRT 100463 LCDR3 S6 NQWQGFPRT 100464LCDR3 T6 NQWQGKPRT 100465 LCDR3 U6 NQWQGNPRT 100466 LCDR3 V6 NQWQGRPRT100467 LCDR3 W6 NQWQGSPRT 100468 LCDR3 X6 NQWQGTPRT 100469 LCDR3 Y6NQWSADPRT 100470 LCDR3 Z6 NQWSAFPRT 100471 LCDR3 A7 NQWSAKPRT 100472LCDR3 B7 NQWSANPRT 100473 LCDR3 C7 NQWSARPRT 100474 LCDR3 D7 NQWSASPRT100475 LCDR3 E7 NQWSATPRT 100476 LCDR3 F7 NQWSGDPRT 100477 LCDR3 G7NQWSGFPRT 100478 LCDR3 H7 NQWSGKPRT 100479 LCDR3 I7 NQWSGNPRT 100480LCDR3 J7 NQWSGRPRT 100481 LCDR3 K7 NQWSGSPRT 100482 LCDR3 L7 NQWSGTPRT

TABLE 2B Non-Limiting Examples of anti- TL1A and anti-DR3 Antibodies HCLC Variable Variable Domain Domain Antibody (SEQ (SEQ Name ID NO) ID NO)A100 115 116 A101 123 124 A102 131 132 A103 142 143 A104 152 153 A105160 161 A106 171 175 A107 171 176 A108 171 177 A109 171 178 A110 171 179A111 171 180 A112 171 181 A113 171 182 A114 172 175 A115 172 176 A116172 177 A117 172 178 A118 172 179 A119 172 180 A120 172 181 A121 172 182A122 173 175 A123 173 176 A124 173 177 A125 173 178 A126 173 179 A127173 180 A128 173 181 A129 173 182 A130 174 175 A131 174 176 A132 174 177A133 174 178 A134 174 179 A135 174 180 A136 174 181 A137 174 182 A138189 194 A139 189 195 A140 189 196 A141 189 197 A142 190 194 A143 190 195A144 190 196 A145 190 197 A146 191 194 A147 191 195 A148 191 196 A149191 197 A150 192 194 A151 192 195 A152 192 196 A153 192 197 A154 193 194A155 193 195 A156 193 196 A157 193 197 A158 204 205 A159 206 207 A160208 209 A161 210 211 A162 212 213 A163 214 215 A164 216 217 A165 218 219A166 220 221 A167 222 223 A168 224 225 A169 226 227 A170 234 235 A171242 243 A172 244 245 A173 252 253 A174 254 255 A175 256 257 A176 282 283A177 290 291 A178 258 271 A179 258 272 A180 258 273 A181 258 274 A182258 275 A183 259 271 A184 259 272 A185 259 273 A186 259 274 A187 259 275A188 260 271 A189 260 272 A190 260 273 A191 260 274 A192 260 275 A193261 271 A194 261 272 A195 261 273 A196 261 274 A197 261 275 A198 262 271A199 262 272 A200 262 273 A201 262 274 A202 262 275 A203 263 271 A204263 272 A205 263 273 A206 263 274 A207 263 275 A208 264 271 A209 264 272A210 264 273 A211 264 274 A212 264 275 A213 265 271 A214 265 272 A215265 273 A216 265 274 A217 265 275 A218 266 271 A219 266 272 A220 266 273A221 266 274 A222 266 275 A223 267 271 A224 267 272 A225 267 273 A226267 274 A227 267 275 A228 268 271 A229 268 272 A230 268 273 A231 268 274A232 268 275 A233 269 271 A234 269 272 A235 269 273 A236 269 274 A237269 275 A238 270 271 A239 270 272 A240 270 273 A241 270 274 A242 270 275

Dosages and Routes of Administration

In general, methods disclosed herein comprise administering atherapeutic agent by oral administration. However, in some instances,methods comprise administering a therapeutic agent by intraperitonealinjection. In some instances, methods comprise administering atherapeutic agent in the form of an anal suppository. In some instances,methods comprise administering a therapeutic agent by intravenous(“i.v.”) administration. It is conceivable that one may also administertherapeutic agents disclosed herein by other routes, such assubcutaneous injection, intramuscular injection, intradermal injection,transdermal injection percutaneous administration, intranasaladministration, intralymphatic injection, rectal administrationintragastric administration, or any other suitable parenteraladministration. In some embodiments, routes for local delivery closer tosite of injury or inflammation are preferred over systemic routes.Routes, dosage, time points, and duration of administrating therapeuticsmay be adjusted. In some embodiments, administration of therapeutics isprior to, or after, onset of either, or both, acute and chronic symptomsof the disease or condition.

An effective dose and dosage of therapeutics to prevent or treat thedisease or condition disclosed herein is defined by an observedbeneficial response related to the disease or condition, or symptom ofthe disease or condition. Beneficial response comprises preventing,alleviating, arresting, or curing the disease or condition, or symptomof the disease or condition (e.g., reduced instances of diarrhea, rectalbleeding, weight loss, and size or number of intestinal lesions orstrictures, reduced fibrosis or fibrogenesis, reduced fibrostenosis,reduced inflammation). In some embodiments, the beneficial response maybe measured by detecting a measurable improvement in the presence,level, or activity, of biomarkers, transcriptomic risk profile, orintestinal microbiome in the subject. An “improvement,” as used hereinrefers to shift in the presence, level, or activity towards a presence,level, or activity, observed in normal individuals (e.g. individuals whodo not suffer from the disease or condition). In instances wherein thetherapeutic agent is not therapeutically effective or is not providing asufficient alleviation of the disease or condition, or symptom of thedisease or condition, then the dosage amount and/or route ofadministration may be changed, or an additional agent may beadministered to the subject, along with the therapeutic agent. In someembodiments, as a patient is started on a regimen of a therapeuticagent, the patient is also weaned off (e.g., step-wise decrease in dose)a second treatment regimen.

Suitable dose and dosage administrated to a subject is determined byfactors including, but no limited to, the particular therapeutic agent,disease condition and its severity, the identity (e.g., weight, sex,age) of the subject in need of treatment, and can be determinedaccording to the particular circumstances surrounding the case,including, e.g., the specific agent being administered, the route ofadministration, the condition being treated, and the subject or hostbeing treated. In general, however, doses employed for adult humantreatment are typically in the range of 0.01 mg-5000 mg per day. In oneaspect, doses employed for adult human treatment are from about 1 mg toabout 1000 mg per day. In one embodiment, the desired dose isconveniently presented in a single dose or in divided doses administeredsimultaneously (or over a short period of time) or at appropriateintervals, for example as two, three, four or more sub-doses per day.Non-limiting examples of effective dosages of for oral delivery of atherapeutic agent include between about 0.1 mg/kg and about 100 mg/kg ofbody weight per day, and preferably between about 0.5 mg/kg and about 50mg/kg of body weight per day. In other instances, the oral deliverydosage of effective amount is about 1 mg/kg and about 10 mg/kg of bodyweight per day of active material. Non-limiting examples of effectivedosages for intravenous administration of the therapeutic agent includeat a rate between about 0.01 to 100 pmol/kg body weight/min. In someembodiments, the daily dosage or the amount of active in the dosage formare lower or higher than the ranges indicated herein, based on a numberof variables in regard to an individual treatment regime. In variousembodiments, the daily and unit dosages are altered depending on anumber of variables including, but not limited to, the activity of thetherapeutic agent used, the disease or condition to be treated, the modeof administration, the requirements of the individual subject, theseverity of the disease or condition being treated, and the judgment ofthe practitioner.

In some embodiments, the administration of the therapeutic agent ishourly, once every 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours,8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours 22hours, 23 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days,8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 1month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8months, 9 months, 10 months, 11 months, 1 year, 2 years, 3 years, 4years, or 5 years, or 10 years. The effective dosage ranges may beadjusted based on subject's response to the treatment. Some routes ofadministration will require higher concentrations of effective amount oftherapeutics than other routes.

In certain embodiments wherein the patient's condition does not improve,upon the doctor's discretion the administration of therapeutic agent isadministered chronically, that is, for an extended period of time,including throughout the duration of the patient's life in order toameliorate or otherwise control or limit the symptoms of the patient'sdisease or condition. In certain embodiments wherein a patient's statusdoes improve, the dose of therapeutic agent being administered may betemporarily reduced or temporarily suspended for a certain length oftime (i.e., a “drug holiday”). In specific embodiments, the length ofthe drug holiday is between 2 days and 1 year, including by way ofexample only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days,12 days, 15 days, 20 days, 28 days, or more than 28 days. The dosereduction during a drug holiday is, by way of example only, by 10%-100%,including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%. In certainembodiments, the dose of drug being administered may be temporarilyreduced or temporarily suspended for a certain length of time (i.e., a“drug diversion”). In specific embodiments, the length of the drugdiversion is between 2 days and 1 year, including by way of exampleonly, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days,15 days, 20 days, 28 days, or more than 28 days. The dose reductionduring a drug diversion is, by way of example only, by 10%-100%,including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%. After asuitable length of time, the normal dosing schedule is optionallyreinstated.

In some embodiments, once improvement of the patient's conditions hasoccurred, a maintenance dose is administered if necessary. Subsequently,in specific embodiments, the dosage or the frequency of administration,or both, is reduced, as a function of the symptoms, to a level at whichthe improved disease, disorder or condition is retained. In certainembodiments, however, the patient requires intermittent treatment on along-term basis upon any recurrence of symptoms.

Toxicity and therapeutic efficacy of such therapeutic regimens aredetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, including, but not limited to, the determinationof the LD50 and the ED50. The dose ratio between the toxic andtherapeutic effects is the therapeutic index and it is expressed as theratio between LD50 and ED50. In certain embodiments, the data obtainedfrom cell culture assays and animal studies are used in formulating thetherapeutically effective daily dosage range and/or the therapeuticallyeffective unit dosage amount for use in mammals, including humans. Insome embodiments, the daily dosage amount of the therapeutic agentdescribed herein lies within a range of circulating concentrations thatinclude the ED50 with minimal toxicity. In certain embodiments, thedaily dosage range and/or the unit dosage amount varies within thisrange depending upon the dosage form employed and the route ofadministration utilized.

Additional Therapeutic Agent

A therapeutic agent may be used alone or in combination with anadditional therapeutic agent. The therapeutic agents may be administeredtogether or sequentially. The combination therapies may be administeredwithin the same day, or may be administered one or more days, weeks,months, or years apart. In some cases, a therapeutic agent providedherein is administered if the subject is determined to be non-responsiveto a first line of therapy, e.g., such as TNF inhibitor. Suchdetermination may be made by treatment with the first line therapy andmonitoring of disease state and/or diagnostic determination that thesubject would be non-responsive to the first line therapy.

In some embodiments, the additional therapeutic agent comprises ananti-TNF therapy, e.g., an anti-TNFα therapy. In some embodiments, theadditional therapeutic agent comprises a second-line treatment to ananti-TNF therapy. In some embodiments, the additional therapeutic agentcomprises an immunosuppressant, or a class of drugs that suppress, orreduce, the strength of the immune system. In some embodiments, theimmunosuppressant is an antibody. Non-limiting examples ofimmunosuppressant therapeutic agents include STELARA® (ustekinumab)azathioprine (AZA), 6-mercaptopurine (6-MP), methotrexate, cyclosporinA. (CsA).

In some embodiments, the additional therapeutic agent comprises aselective anti-inflammatory drug, or a class of drugs that specificallytarget pro-inflammatory molecules in the body. In some embodiments, theanti-inflammatory drug comprises an antibody. In some embodiments, theanti-inflammatory drug comprises a small molecule. Non-limiting examplesof anti-inflammatory drugs include ENTYVIO (vedolizumab),corticosteroids, aminosalicylates, mesalamine, balsalazide (Colazal) andolsalazine (Dipentum).

In some embodiments, the additional therapeutic agent comprises a stemcell therapy. The stem cell therapy may be embryonic or somatic stemcells. The stem cells may be isolated from a donor (allogeneic) orisolated from the subject (autologous). The stem cells may be expandedadipose-derived stem cells (eASCs), hematopoietic stem cells (HSCs),mesenchymal stem (stromal) cells (MSCs), or induced pluripotent stemcells (iPSCs) derived from the cells of the subject. In someembodiments, the therapeutic agent comprises Cx601/Alofisel®(darvadstrocel).

In some embodiments, the additional therapeutic agent comprises a smallmolecule. The small molecule may be used to treat inflammatory diseasesor conditions, or fibrostenonic or fibrotic disease. Non-limitingexamples of small molecules include Otezla® (apremilast), alicaforsen,or ozanimod (RPC-1063).

The additional therapeutic agent may comprise an antimycotic agent. Insome instances, the antimycotic agent comprises an active agent thatinhibits growth of a fungus. In some instances, the antimycotic agentcomprises an active agent that kills a fungus. In some embodiments, theantimycotic agent comprises polyene, an azole, an echinocandin, anflucytosine, an allylamine, a tolnaftate, or griseofulvin, or acombination thereof. In other embodiments, the azole comprises triazole,imidazole, clotrimazole, ketoconazole, itraconazole, terconazole,oxiconazole, miconazole, econazole, tioconazole, voriconazole,fluconazole, isavuconazole, itraconazole, pramiconazole, ravuconazole,or posaconazole. In some other embodiments, the polyene comprisesamphotericin B, nystatin, or natamycin. In yet other embodiments, theechinocandin comprises caspofungin, anidulafungin, or micafungin. Invarious other embodiments, the allylamine comprises naftifine orterbinafine.

The additional therapeutic agent may comprise an agonist or anantagonist of therapeutic target. Non-limiting therapeutic targetsinclude Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4(MAP4K4), Prostaglandin EReceptor 4 (PTGER4), Interleukin 18 Receptor 1(IL18R1), Interleukin 18 Receptor Accessory Protein (IL18RAP), AdenylateCyclase 7 (ADCY7), B Lymphoid Tyrosine Kinase (BLK), G Protein-CoupledReceptor 65 (GPR65), Sprouty Related EVH1 Domain Containing 2 (SPRED2),and Src Kinase Associated Phosphoprotein 2 (SKAP2). Non-limitingexamples of MAP4K4 modulators include GNE-220 and PF-6260933.Non-limiting examples of PTGER4 modulators include grapiprant(CJ-023,423), ONO-AE3-208, GW627368X, AH23848, ONO-AE2-227, ONO-AE1-734,AGN205203, rivenprost (ONO-4819), CJ-023,423, and BGC20-1531. Exemplarymodulators of PFKFB3 include, but are not limited to3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO),1-(4-pyridiny)-3-(2-quinoliny)-2-propen-1-one (PFK15),5-triazolo-2-arylpyridazinone,1251-(3-pyridinyl)-3-(2-quinolinyl)-2-propen-1-one (PQP), 126 5, 6, 7,8-tetrahydroxy-2-(4-hydroxyphenyl) chrome-4-one (N4A), and 7,8-dihydroxy-3-(4-hydroxyphenyl) chromen-4-one (YN1). Non-limitingmodulators of ADCY7 include forskolin and colforsin daropate.Non-limiting examples of GPR65 modulators include BTB09089(3-[(2,4-dichlorophenyl)methylsulfanyl]-1,6-dimethylpyridazino[4,5-e][1,3,4]thiadiazin-5-one),and ZINC62678696.

In some embodiments, the therapeutic agent comprises an agonist of JanusKinase 1 (JAK1). Non-limiting examples of JAK1 inhibitors includeRuxolitinib (INCB018424), S-Ruxolitinib (INCB018424), Baricitinib(LY3009104, INCB028050), Filgotinib (GLPG0634), Momelotinib (CYT387),Cerdulatinib (PRT062070, PRT2070), LY2784544, NVP-BSK805, 2HCl,Tofacitinib (CP-690550, Tasocitinib), XL019, Pacritinib (SB1518), or ZM39923 HCl.

The therapeutic agent targeting the above genes or gene expressionproducts may be an antibody or antigen binding fragment thereof. Thetherapeutic agent may be a small molecule. The therapeutic agent may bea peptide or a protein. The therapeutic agent may be an agonist, orpartial agonist. The therapeutic agent may be an allosteric modulator,such as a positive allosteric modulator (PAM). The therapeutic agent maybe an antagonist, or partial antagonist. The therapeutic agent may be aninverse agonist. The therapeutic agent may be a negative allostericmodulator (NAM).

Disclosed herein are additional therapeutic agents comprising modulatorsof Receptor Interacting Serine/Threonine Kinase 2 (RIPK2) (Entrez GeneID: 8767) activity or expression that are useful for the treatment of aninflammatory, fibrotic, and/or fibrostenotic disease or condition. Insome embodiments, the inflammatory disease comprises inflammatory boweldisease (IBD), Crohn's disease (CD), and/or ulcerative colitis (UC). Insome embodiments, a modulator of RIPK2 activity or expression comprisesan antagonist or a partial antagonist of RIPK2. In some embodiments, theRIPK2 antagonist or partial antagonist comprises an antibody orantigen-binding fragment, or a small molecule.

In some embodiments, the RIPK2 antagonist or partial antagonistcomprises a type I RIPK2 inhibitor effective to bind to the ATP bindingpocket of an active conformation of the RIPK2 kinase domain. In someembodiments, the RIPK2 antagonist or partial antagonist comprises a typeIM RIPK2 inhibitor effective to bind to the ATP binding pocket of aninactive conformation of the RIPK2 kinase domain without displacing theRIPK2 kinase activation segment. In some embodiments, the RIPK2antagonist or partial antagonist comprises a type II RIPK2 inhibitoreffective to displace a RIPK2 kinase activation segment. In someembodiments, the RIPK2 antagonist or partial antagonist comprises a typeIII RIPK2 inhibitor effective to bind an allosteric site of RIPK2located in the cleft between the small and large lobes adjacent to theATP binding pocket. In some embodiments, the RIPK2 antagonist or partialantagonist comprises a type IV RIPK2 inhibitor effective to bind anallosteric site of RIPK2 located outside of the cleft and thephosphoacceptor region. In some embodiments, the RIPK2 antagonist orpartial antagonist comprises a type V RIPK2 inhibitor effective to spantwo regions of the RIPK2 kinase domain. In some embodiments, the RIPK2antagonist or partial antagonist comprises a type VI RIPK2 inhibitoreffective to form a covalent adduct with RIPK2. In some embodiments, theRIPK2 antagonist or partial antagonist comprises a RIPK2 inhibitoreffective to inhibit RIPK2 ubiquitination. In some embodiments, theRIPK2 antagonist or partial antagonist comprises a RIPK2 inhibitoreffective to inhibit RIPK2 autophosphorylation. In some embodiments, theRIPK2 antagonist or partial antagonist comprises a RIPK2 inhibitoreffective to block NOD-dependent tumor necrosis factor productionwithout affecting lipopolysaccharide-dependent pathways. In someembodiments, the RIPK2 antagonist or partial antagonist comprisesponatinib, sorafenib, regorafenib, gefitinib, or erlotinib. In someembodiments, the RIPK2 antagonist or partial antagonist comprisesGSK2983559, GSK583, Inhibitor 7, Biaryl Urea, CSR35, CSLP37, CSLP43,RIPK2 inhibitor 1, CS6, PP2, WEHI-345, SB203580, OD36, OD38, RIPK2-IN-8,RIPK2-IN-1, or RIPK2-IN-2, or any combination thereof.

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (I) or a pharmaceutically acceptable salt orisotopic variant thereof:

-   -   wherein    -   Ring A is C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl,        or 6- to 10-membered aryl;    -   X is N or CR⁴;    -   R¹ and R² are independently —H, halogen, —OH, —OR⁵, —CN,        —N(R⁶)₂, —NR⁶C(O)R⁵, —C(O)OR⁵, —C(O)N(R⁶)₂, C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-OH,        —C₁₋₆alkyl-OR⁵, —C₁₋₆alkyl-N(R⁶)₂, —O—C₁₋₆alkyl,        —O—C₁₋₆alkyl-OH, —O—C₁₋₆alkyl-OR⁵, —O—C₁₋₆alkyl-N(R⁶)₂, or        —S(═O)₂R⁵;    -   each R³ is independently —H, halogen, —NO₂, —CN, —OH, —OR⁵,        —SR⁵, —N(R⁶)₂, —S(O)R⁵, —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵, —S(═O)₂N(R⁶)₂,        —C(O)R⁵, —C(O)OR⁵, —OC(O)R⁵, —C(O)N(R⁶)₂, —OC(O)N(R⁶)₂,        —NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁵, —NR⁶C(O)OR⁵, C₁₋₆ alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆heteroalkyl,        —O—C₁₋₆alkyl, C₃₋₈ cycloalkyl, C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, 6- to 10-membered aryl, or —O— phenyl, wherein        each alkyl, haloalkyl, heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is optionally substituted        with one or more R⁷;    -   R⁴ is —H, halogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆ alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, or        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein the alkyl, haloalkyl,        cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl are        optionally substituted;    -   each R⁵ is independently —H, C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl,        —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl, —C₁₋₆alkyl-phenyl,        C₂₋₉heterocycloalkyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, or —C₁₋₆alkyl-C₂₋₉heteroaryl;    -   each R⁶ is independently —H, C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl,        —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl, —C₁₋₆alkyl-phenyl, or        C₂₋₉heteroaryl; or        -   two R⁶ substituents are taken together with the nitrogen            atom to which they are attached to form a 5- or 6-membered            heterocycle; and    -   R⁷ is —H, halogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆ alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, or        —C₁₋₆alkyl-C₂₋₉heteroaryl; and    -   n is 0, 1, 2, 3, 4, or 5.

In some embodiments of a compound of Formula (I), Ring A isC₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, or 6- to10-membered aryl. In some embodiments of a compound of Formula (I), RingA is C₃₋₇heteroaryl or 6-membered aryl. In some embodiments of acompound of Formula (I), Ring A is pyrrazolyl. In some embodiments of acompound of Formula (I), Ring A is C₇heteroaryl. In some embodiments ofa compound of Formula (I), Ring A is phenyl.

In some embodiments, for a compound of Formula (I), X is N or CR⁴. Insome embodiments, for a compound of Formula (I), X is N or CH. In someembodiments, for a compound of Formula (I), X is N. In some embodiments,for a compound of Formula (I), X is CH.

In some embodiments, for a compound of Formula (I), R¹ is —H, halogen,—OH, —CN, —N(R⁶)₂, —NR⁶C(O)R⁵, —C(O)OR⁵, —C(O)N(R⁶)₂, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, —C₁₋₆alkyl-OH,—C₁₋₆alkyl-OR⁵, —C₁₋₆alkyl-N(R⁶)₂, —O—C₁₋₆alkyl, —O—C₁₋₆alkyl-OH,—O—C₁₋₆alkyl-OR⁵, —O—C₁₋₆alkyl-N(R⁶)₂, or —S(═O)₂R⁵. In someembodiments, for a compound of Formula (I), R¹ is C₁₋₆alkyl,C₂₋₆alkenyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁵, —C₁₋₆alkyl-N(R⁶)₂,—O—C₁₋₆alkyl, —O—C₁₋₆alkyl-OH, —O—C₁₋₆alkyl-OR⁵, —O—C₁₋₆alkyl-N(R⁶)₂, or—S(═O)₂R⁵. In some embodiments, for a compound of Formula (I), R¹ is—O—C₁₋₆alkyl, —O—C₁₋₆alkyl-OR⁵, —O—C₁₋₆ alkyl-N(R⁶)₂, or —S(═O)₂R⁵. Insome embodiments, for a compound of Formula (I), R¹ is —O—C₁₋₆ alkyl. Insome embodiments, for a compound of Formula (I), R¹ is —OCH₃. In someembodiments, for a compound of Formula (I), R¹ is —O—C₁₋₆alkyl-OR⁵. Insome embodiments, for a compound of Formula (I), R¹ is —OCH₂CH₂OCH₃. Insome embodiments, for a compound of Formula (I), R¹ is—O—C₁₋₆alkyl-N(R⁶)₂. In some embodiments, for a compound of Formula (I),R¹ is —OCH₂CH₂CH₂morpholine. In some embodiments, for a compound ofFormula (I), R¹ is —S(═O)₂R⁵. In some embodiments, for a compound ofFormula (I), R¹ is —S(═O)₂tert-butyl.

In some embodiments, for a compound of Formula (I), R² is —H, halogen,—OH, —CN, —N(R⁶)₂, —NR⁶C(O)R⁵, —C(O)OR⁵, —C(O)N(R⁶)₂, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, —C₁₋₆alkyl-OH,—C₁₋₆alkyl-OR⁵, —C₁₋₆alkyl-N(R⁶)₂, —O—C₁₋₆alkyl, —O—C₁₋₆alkyl-OH,—O—C₁₋₆alkyl-OR⁵, —O—C₁₋₆alkyl-N(R⁶)₂, or —S(═O)₂R⁵. In someembodiments, for a compound of Formula (I), R² is —H, —O—C₁₋₆alkyl,—O—C₁₋₆alkyl-OR⁵, or —O—C₁₋₆alkyl-OH. In some embodiments, for acompound of Formula (I), R² is —H. In some embodiments, for a compoundof Formula (I), R² is —O—C₁₋₆alkyl. In some embodiments, for a compoundof Formula (I), R² is —OCH₃. In some embodiments, for a compound ofFormula (I), R² is —O—C₁₋₆alkyl-OR⁵. In some embodiments, for a compoundof Formula (I), R² is —OCH₂CH₂OCH₃. In some embodiments, for a compoundof Formula (I), R² is —O—C₁₋₆alkyl-OH. In some embodiments, for acompound of Formula (I), R² is —OCH₂CH₂OH.

In some embodiments, for a compound of Formula (I), R³ is —H, halogen,—NO₂, —CN, —OH, —OR⁵, —SR⁵, —N(R⁶)₂, —S(O)R⁵, —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵,—S(═O)₂N(R⁶)₂, —C(O)R⁵, —C(O)OR⁵, —OC(O)R⁵, —C(O)N(R⁶)₂, —OC(O)N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁵, —NR⁶C(O)OR⁵, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆heteroalkyl, —O—C₁₋₆alkyl,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, 6- to 10-memberedaryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more R⁷. In some embodiments, for a compound ofFormula (I), R³ is —H, halogen, C₁₋₆alkyl, C₂₋₆alkynyl, or —O-phenyl. Insome embodiments, for a compound of Formula (I), R³ is —H. In someembodiments, for a compound of Formula (I), R³ is —Cl. In someembodiments, for a compound of Formula (I), R³ is —F. In someembodiments, for a compound of Formula (I), R³ is —CH₃. In someembodiments, for a compound of Formula (I), R³ is —CCH. In someembodiments, for a compound of Formula (I), R³ is —O-phenyl.

In some embodiments, for a compound of Formula (I), n is 0, 1, 2, or 3.In some embodiments, for a compound of Formula (I), n is 1, 2, or 3. Insome embodiments, for a compound of Formula (I), n is 1 or 2. In someembodiments, for a compound of Formula (I), n is 0. In some embodiments,for a compound of Formula (I), n is 1. In some embodiments, for acompound of Formula (I), n is 2. In some embodiments, for a compound ofFormula (I), n is 3.

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (Ia) or a pharmaceutically acceptable salt orisotopic variant thereof:

wherein;

-   -   each R³ is independently —H, halogen, —C≡CH, or —O-aryl; and    -   each R⁵ is independently C₁₋₆ alkyl, —C₁₋₆alkyl-O—C₁₋₆alkyl, or        —C₁₋₆alkyl-heterocycloalkyl.

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (Ia) or a pharmaceutically acceptable salt orisotopic variant thereof:

wherein;

-   -   each R³ is independently —H, —Cl, —F, —C≡CH, or —O-phenyl; and    -   each R⁵ is independently —CH₃, —CH₂CH₂OCH₃, or        —CH₂CH₂CH₂morpholine.

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (Ib) or a pharmaceutically acceptable salt orisotopic variant thereof:

wherein;

-   -   Ring A is C₃₋₇heteroaryl;    -   X is N or CH;    -   R² is —H, —OC₁₋₆alkyl, or —O—C₁₋₆alkyl-OH;    -   each R³ is independently —H, —C₁₋₆alkyl, or halogen; and    -   n is 0, 1, or 2.

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (Ib) or a pharmaceutically acceptable salt orisotopic variant thereof:

wherein;

-   -   Ring A is C₃₋₇heteroaryl;    -   X is N or CH;    -   R² is —H, —OCH₃, or —OCH₂CH₂OH;    -   each R³ is independently —H, —CH₃, or —F; and    -   n is 0, 1, or 2.

In some embodiments a compound of Formula (I) or a pharmaceuticallyacceptable salt or isotopic variant thereof has the structure of:

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (II) or a pharmaceutically acceptable salt orisotopic variant thereof:

wherein

-   -   Rings A and B are independently C₃₋₈cycloalkyl,        C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, or 6- to 10-membered aryl;    -   X¹, X², and X³ are independently N or CR⁴;    -   Y¹ and Y² are independently a bond, —O—, —S—, —C(R⁵)₂, —NR⁶—,        —NR⁶C(O)—, —C(O)NR⁶—, or —NR⁶C(O)NR⁶—;    -   each R¹ and R² is independently —H, halogen, —NO₂, —CN, —OH,        —OR⁵, —SR⁵, —N(R⁶)₂, —S(O)R⁵, —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵,        —S(═O)₂N(R⁶)₂, —SCH₂C(O)OR⁵, —C(O)R⁵, —C(O)OR⁵, —OC(O)R⁵,        —C(O)N(R⁶)₂, —OC(O)N(R⁶)₂, —NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁵,        —NR⁶C(O)OR⁵, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,        C₁₋₆heteroalkyl, —O—C₁₋₆alkyl, C₃₋₈cycloalkyl,        C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, 6- to 10-membered aryl, or        —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally        substituted with one or more R⁷;    -   each R⁴ is independently —H, halogen, —N(R⁶)₂, —NO₂, C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl, —C₁₋₆alkyl-phenyl,        C₂₋₉heterocycloalkyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, or —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein the alkyl,        haloalkyl, cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl        are optionally substituted;    -   each R⁵ is independently —H, C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl,        —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl, —C₁₋₆alkyl-phenyl,        C₂₋₉heterocycloalkyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, or —C₁₋₆alkyl-C₂₋₉heteroaryl;    -   each R⁶ is independently —H, C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl,        —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl, —C₁₋₆alkyl-phenyl, or        C₂₋₉heteroaryl; or        -   two R⁶ are taken together with the nitrogen atom to which            they are attached to form a 5- or 6-membered heterocycle;            and    -   R⁷ is —H, halogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆ alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, or        —C₁₋₆alkyl-C₂₋₉heteroaryl; and    -   m and n are each independently 0, 1, 2, 3, 4, or 5.

In some embodiments, for a compound of Formula (II), Rings A and B areindependently C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, or6- to 10-membered aryl. In some embodiments, for a compound of Formula(II), Rings A and B are independently C₂₋₉heteroaryl or 6- to10-membered aryl. In some embodiments, for a compound of Formula (II),Ring A is phenyl. In some embodiments, for a compound of Formula (II),Ring A is pyridyl. In some embodiments, for a compound of Formula (II),Ring A is furanyl. In some embodiments, for a compound of Formula (II),Ring B is phenyl. In some embodiments, for a compound of Formula (II),Ring B is pyrrazolyl. In some embodiments, for a compound of Formula(II), Ring B is pyridyl. In some embodiments, for a compound of Formula(II), Ring B is isoxazolyl. In some embodiments, for a compound ofFormula (II), Ring A is phenyl and Ring B is pyrrazolyl. In someembodiments, for a compound of Formula (II), Ring A is phenyl and Ring Bis phenyl. In some embodiments, for a compound of Formula (II), Ring Ais phenyl and Ring B is pyridyl. In some embodiments, for a compound ofFormula (II), Ring A is pyridyl and Ring B is phenyl. In someembodiments, for a compound of Formula (II), Ring A is pyridyl and RingB is isoxazolyl. In some embodiments, for a compound of Formula (II),Ring A is isoxazoylyl and Ring B is pyridyl. In some embodiments, for acompound of Formula (II), Ring A is furanyl and Ring B is phenyl.

In some embodiments, for a compound of Formula (II), X¹, X², and X³ areindependently N or CR⁴. In some embodiments, for a compound of Formula(II), X¹ is CH. In some embodiments, for a compound of Formula (II), X¹is CF. In some embodiments, for a compound of Formula (II), X¹ is CCH₃.In some embodiments, for a compound of Formula (II), X¹ is CNH₂. In someembodiments, for a compound of Formula (II), X¹ is N. In someembodiments, for a compound of Formula (II), X² is CH. In someembodiments, for a compound of Formula (II), X² is CF. In someembodiments, for a compound of Formula (II), X² is N. In someembodiments, for a compound of Formula (II), X² is C—N-methylpyrazine.In some embodiments, for a compound of Formula (II), X³ is CH. In someembodiments, for a compound of Formula (II), X³ is N. In someembodiments, for a compound of Formula (II), X¹ is CF and X² and X³ areCH. In some embodiments, for a compound of Formula (II), X² is CF and X¹and X³ are CH. In some embodiments, for a compound of Formula (II), X¹,X², and X³ are CH. In some embodiments, for a compound of Formula (II),X¹ is CCH₃ and X² and X³ are CH. In some embodiments, for a compound ofFormula (II), X¹ is CNH₂, X² is N, and X³ is CH. In some embodiments,for a compound of Formula (II), X² is C—N-methylpyrazine and X¹ and X³are N.

In some embodiments, for a compound of Formula (II), Y¹ and Y² areindependently a bond, —O—, —S—, —C(R⁵)₂, —NR⁶—, —NR⁶C(O)—, —C(O)NR⁶—, or—NR⁶C(O)NR⁶—. In some embodiments, for a compound of Formula (II), Y¹ is—NR⁶C(O)—. In some embodiments, for a compound of Formula (II), Y¹ is—O—. In some embodiments, for a compound of Formula (II), Y¹ is—NR⁶C(O)NR⁶—. In some embodiments, for a compound of Formula (II), Y¹ isa bond. In some embodiments, for a compound of Formula (II), Y¹ is—NR⁶—. In some embodiments, for a compound of Formula (II), Y² is—NR⁶C(O)—. In some embodiments, for a compound of Formula (II), Y² is—O—. In some embodiments, for a compound of Formula (II), Y² is—NR⁶C(O)NR⁶—. In some embodiments, for a compound of Formula (II), Y² isa bond. In some embodiments, for a compound of Formula (II), Y¹ is —S—.In some embodiments, for a compound of Formula (II), Y¹ and Y² are—NHC(O)—. In some embodiments, for a compound of Formula (II), Y¹ is —O—and Y² is —NHC(O)NH—. In some embodiments, for a compound of Formula(II), Y¹ is —NHC(O)NH— and Y² is —O—. In some embodiments, for acompound of Formula (II), Y¹ and Y² are bonds. In some embodiments, fora compound of Formula (II), Y¹ is —NH— and Y² is —S—.

In some embodiments, for a compound of Formula (II), R¹ is —H, halogen,—NO₂, —CN, —OH, —OR⁵, —SR⁵, —N(R⁶)₂, —S(O)R⁵, —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵,—S(═O)₂N(R⁶)₂, —C(O)R⁵, —C(O)OR⁵, —OC(O)R⁵, —C(O)N(R⁶)₂, —OC(O)N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁵, —NR⁶C(O)OR⁵, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, C₆heteroalkyl, —O—C₁₋₆alkyl, C₃₋₈cycloalkyl,C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, 6- to 10-membered aryl, or—O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is optionally substituted withone or more R⁷. In some embodiments, for a compound of Formula (II), R¹is —Cl. In some embodiments, for a compound of Formula (II), R¹ is —F.In some embodiments, for a compound of Formula (II), R¹ is —C(O)NHCH₃.In some embodiments, for a compound of Formula (II), R¹ is2-methylpyrrazolyl. In some embodiments, for a compound of Formula (II),R¹ is N-methylimidazolyl. In some embodiments, for a compound of Formula(II), R¹ is tert-butyl. In some embodiments, for a compound of Formula(II), R¹ is —NHC(O)cyclopropyl. In some embodiments, for a compound ofFormula (II), R¹ is —SCH₂C(O)OH. In some embodiments, for a compound ofFormula (II), R¹ is —OCH₃. In some embodiments, for a compound ofFormula (II), R¹ is —NHS(═O)₂CH₂CH₂CH₃.

In some embodiments, for a compound of Formula (II), R² is —H, halogen,—NO₂, —CN, —OH, —OR⁵, —SR⁵, —N(R⁶)₂, —S(O)R⁵, —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵,—S(═O)₂N(R⁶)₂, —C(O)R⁵, —C(O)OR⁵, —OC(O)R⁵, —C(O)N(R⁶)₂, —OC(O)N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁵, —NR⁶C(O)OR⁵, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆heteroalkyl, —O—C₁₋₆alkyl,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, 6- to 10-memberedaryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more R⁷. In some embodiments, for a compound ofFormula (II), R² is —Cl. In some embodiments, for a compound of Formula(II), R² is —F. In some embodiments, for a compound of Formula (II), R²is —C(O)NHCH₃. In some embodiments, for a compound of Formula (II), R¹is 2-methylpyrrazolyl. In some embodiments, for a compound of Formula(II), R¹ is N-methylimidazolyl. In some embodiments, for a compound ofFormula (II), R² is —CH₂-(2-iso-propylimidazole). In some embodiments,for a compound of Formula (II), R² is tert-butyl. In some embodiments,for a compound of Formula (II), R² is —CH₃. In some embodiments, for acompound of Formula (II), R² is —C(O)NHCH₃. In some embodiments, for acompound of Formula (II), R² is pyrazinyl.

In some embodiments, for a compound of Formula (II), m is 1 or 2. Insome embodiments, for a compound of Formula (II), m is 1. In someembodiments, for a compound of Formula (II), m is 2. In someembodiments, for a compound of Formula (II), n is 1 or 2. In someembodiments, for a compound of Formula (II), n is 1. In someembodiments, for a compound of Formula (II), n is 2.

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (IIa) or a pharmaceutically acceptable salt orisotopic variant thereof:

-   -   wherein    -   Ring A is phenyl or isoxazolyl;    -   each R¹ is independently C₁₋₆alkyl, halogen, —C₁₋₆fluoroalkyl,        or —S—C₁₋₆alkyl-C(O)OH;    -   R² is —H or —C(O)NHCH₃;    -   R⁴ is —H or halogen; and    -   m is 1 or 2.

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (IIa) or a pharmaceutically acceptable salt orisotopic variant thereof:

-   -   wherein    -   Ring A is phenyl or isoxazolyl;    -   each R¹ is independently tert-butyl, —Cl, —F, —CF₃, or        —SCH₂C(O)OH;    -   R² is —H or —C(O)NHCH₃;    -   R⁴ is —H or halogen; and    -   m is 1 or 2.

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (IIb) or a pharmaceutically acceptable salt orisotopic variant thereof:

-   -   wherein    -   R¹ is halogen or —OR⁵.

In some embodiments a compound of Formula (II) or a pharmaceuticallyacceptable salt or isotopic variant thereof has the structure of:

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (III) or a pharmaceutically acceptable salt orisotopic variant thereof:

-   -   wherein    -   X is N or CR⁴;    -   Y is a bond, —O—, —S—, —C(R⁵)₂, —NR⁶—, —NR⁶C(O)—, —C(O)NR⁶—, or        —NR⁶C(O)NR⁶—;    -   R¹ is —H, halogen, —OH, —CN, —N(R⁶)₂, —NR⁶C(O)R⁵, —C(O)OR⁵,        —C(O)N(R⁶)₂, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁵,        —C₁₋₆alkyl-N(R⁶)₂, —O—C₁₋₆alkyl, —O—C₁₋₆alkyl-OH,        —O—C₁₋₆alkyl-OR⁵, —O—C₁₋₆alkyl-N(R⁶)₂, or —S(═O)₂R⁵;    -   R² and R³ are independently —H, halogen, —NO₂, —CN, —OH, —OR⁵,        —SR⁵, —N(R⁶)₂, —S(O)R⁵, —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵, —S(═O)₂N(R⁶)₂,        —C(O)R⁵, —C(O)OR⁵, —OC(O)R⁵, —C(O)N(R⁶)₂, —OC(O)N(R⁶)₂,        —NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁵, —NR⁶C(O)OR⁵, C₁₋₆ alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆heteroalkyl,        —O—C₁₋₆alkyl, C₃₋₈ cycloalkyl, C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, 6- to 10-membered aryl, or —O— phenyl, wherein        each alkyl, haloalkyl, heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is optionally substituted        with one or more R⁷; or    -   R² and R³ are taken together with the atoms to which they are        attached to form an optionally substituted C₃₋₈cycloalkyl; and    -   R⁴ is hydrogen, halogen, —N(R⁶)₂, —NO₂, C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl, —C₁₋₆alkyl-phenyl,        C₂₋₉heterocycloalkyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, or —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein the alkyl,        haloalkyl, cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl        are optionally substituted;    -   R⁵ is —H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, or        —C₁₋₆alkyl-C₂₋₉heteroaryl;    -   each R⁶ is independently —H, C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl,        —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl, —C₁₋₆alkyl-phenyl, or        C₂₋₉heteroaryl; or        -   two R⁶ substituents are taken together with the nitrogen            atom to which they are attached to form a 5- or 6-membered            heterocycle; and    -   R⁷ is —H, halogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, or        —C₁₋₆alkyl-C₂₋₉heteroaryl.

In some embodiments, for a compound of Formula (III), X is N or CR⁴. Insome embodiments, for a compound of Formula (III), X is N and CH. Insome embodiments, for a compound of Formula (III), X is N. In someembodiments, for a compound of Formula (III), X is CH.

In some embodiments, for a compound of Formula (III), Y is a bond, —O—,—S—, —C(R⁵)₂, —NR⁶—, —NR⁶C(O)—, —C(O)NR⁶—, or —NR⁶C(O)NR⁶—. In someembodiments, for a compound of Formula (III), Y is —NR⁶C(O)— or—C(O)NR⁶—. In some embodiments, for a compound of Formula (III), Y is—NHC(O)—. In some embodiments, for a compound of Formula (III), Y is—C(O)NH—.

In some embodiments, for a compound of Formula (III), R¹ is —H, halogen,—OH, —CN, —N(R⁶)₂, —NR⁶C(O)R⁵, —C(O)OR⁵, —C(O)N(R⁶)₂, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, —C₁₋₆alkyl-OH,—C₁₋₆alkyl-OR⁵, —Cl₆alkyl-N(R⁶)₂, —O—C₁₋₆alkyl, —O—C₁₋₆alkyl-OH,—O—C₁₋₆alkyl-OR⁵, —O—C₁₋₆alkyl-N(R⁶)₂, or —S(═O)₂R⁵. In someembodiments, for a compound of Formula (III), R¹ is —H, halogen, —OH,—CN, —N(R⁶)₂, C₁₋₆alkyl, C₂₋₆alkynyl, or C₃₋₈cycloalkyl. In someembodiments, for a compound of Formula (III), R¹ is C₁₋₆alkyl. In someembodiments, for a compound of Formula (III), R¹ is —CH₃. In someembodiments, for a compound of Formula (III), R¹ is tert-butyl.

In some embodiments, for a compound of Formula (III), R² is —H, halogen,—NO₂, —CN, —OH, —OR⁵, —SR⁵, —N(R⁶)₂, —S(O)R⁵, —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵,—S(═O)₂N(R⁶)₂, —C(O)R⁵, —C(O)OR⁵, —OC(O)R⁵, —C(O)N(R⁶)₂, —OC(O)N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁵, —NR⁶C(O)OR⁵, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆heteroalkyl, —O—C₁₋₆alkyl,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, 6- to 10-memberedaryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more R⁷, or R² and R³ are taken together withthe atoms to which they are attached to form an optionally substitutedC₃₋₈cycloalkyl. In some embodiments, for a compound of Formula (III), R²is —H, halogen, —NO₂, —CN, —OH, —OR⁵, C₁₋₆alkyl, C₁₋₆ haloalkyl,C₁₋₆heteroalkyl, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl,or 6- to 10-membered aryl, or R² and R³ are taken together with theatoms to which they are attached to form an optionally substitutedC₃₋₈cycloalkyl. In some embodiments, for a compound of Formula (III), R²is C₁₋₆alkyl, C₁₋₆haloalkyl, or C₃₋₈cycloalkyl, or R² and R³ are takentogether with the atoms to which they are attached to form an optionallysubstituted C₃₋₈cycloalkyl. In some embodiments, for a compound ofFormula (III), R² is —CH₃, —CF₃, or cyclopropyl, or R² and R³ are takentogether with the atoms to which they are attached to form an optionallysubstituted C₃₋₈ cycloalkyl. In some embodiments, for a compound ofFormula (III), R² is —CH₃, —CF₃, or cyclopropyl. In some embodiments,for a compound of Formula (III), R² is —CH₃. In some embodiments, for acompound of Formula (III), R² is —CF₃. In some embodiments, for acompound of Formula (III), R² is cyclopropyl. In some embodiments, for acompound of Formula (III), R² and R³ are taken together with the atomsto which they are attached to form a C₅ cycloalkyl. In some embodiments,for a compound of Formula (III), R² and R³ are taken together with theatoms to which they are attached to form a C₅ cycloalkyl substitutedwith an N-methylpiperazine.

In some embodiments, for a compound of Formula (III), R³ is —H, halogen,—NO₂, —CN, —OH, —OR⁵, —SR⁵, —N(R⁶)₂, —S(O)R⁵, —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵,—S(═O)₂N(R⁶)₂, —C(O)R⁵, —C(O)OR⁵, —OC(O)R⁵, —C(O)N(R⁶)₂, —OC(O)N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁵, —NR⁶C(O)OR⁵, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆heteroalkyl, —O—C₁₋₆alkyl,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, 6- to 10-memberedaryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more R⁷, or R² and R³ are taken together withthe atoms to which they are attached to form an optionally substitutedC₃₋₈cycloalkyl. In some embodiments, for a compound of Formula (III), R³is —H, halogen, —CN, —OR⁵, —N(R⁶)₂, —S(═O)₂R⁵, —C(O)R⁵, —C(O)OR⁵,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁵, —NR⁶C(O)OR⁵, C₁₋₆alkyl, C₁₋₆heteroalkyl,C₂₋₉heterocycloalkyl, or C₂₋₉heteroaryl, wherein each alkyl,heteroalkyl, heterocycloalkyl, and heteroaryl is optionally substitutedwith one or more R⁷, or R² and R³ are taken together with the atoms towhich they are attached to form an optionally substitutedC₃₋₈cycloalkyl. In some embodiments, for a compound of Formula (III), R³is C₁₋₆alkyl substituted with C₂₋₉heterocycloalkyl. In some embodiments,for a compound of Formula (III), R³ is CH₂—N— methylpiperazine. In someembodiments, for a compound of Formula (III), R² and R³ are takentogether with the atoms to which they are attached to form a C₅cycloalkyl. In some embodiments, for a compound of Formula (III), R² andR³ are taken together with the atoms to which they are attached to forma C₅ cycloalkyl substituted with an N-methylpiperazine.

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (III) or a pharmaceutically acceptable salt orisotopic variant thereof:

-   -   wherein    -   R¹ is C₁₋₆alkyl.

In some embodiments a compound of Formula (III) or a pharmaceuticallyacceptable salt or isotopic variant thereof has the structure of:

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (IV) or a pharmaceutically acceptable salt orisotopic variant thereof:

-   -   wherein    -   Ring A is C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl,        or 6- to 10-membered aryl;    -   Y is a bond, —O—, —S—, —C(R⁵)₂—, —NR⁶—, —NR⁶C(O)—, —C(O)NR⁶—, or        —NR⁶C(O)NR⁶—;    -   R¹ is —H, halogen, —OH, —CN, —N(R⁶)₂, —NR⁶C(O)R⁵, —C(O)OR⁵,        —C(O)N(R⁶)₂, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁵,        —C₁₋₆alkyl-N(R⁶)₂, —O—C₁₋₆alkyl, —O—C₁₋₆alkyl-OH,        —O—C₁₋₆alkyl-OR⁵, —O—C₁₋₆alkyl-N(R⁶)₂, or —S(═O)₂R⁵;    -   R² is —H, halogen, —NO₂, —CN, —OH, —OR⁵, —SR⁵, —N(R⁶)₂, —S(O)R⁵,        —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵, —S(═O)₂N(R⁶)₂, —C(O)R⁵, —C(O)OR⁵,        —OC(O)R⁵, —C(O)N(R⁶)₂, —OC(O)N(R⁶)₂, —NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁵,        —NR⁶C(O)OR⁵, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,        C₁₋₆heteroalkyl, —O—C₁₋₆alkyl, C₃₋₈cycloalkyl,        C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, 6- to 10-membered aryl, or        —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally        substituted with one or more R⁷;    -   R⁵ is —H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, or        —C₁₋₆alkyl-C₂₋₉heteroaryl;    -   each R⁶ is independently —H, C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl,        —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl, —C₁₋₆alkyl-phenyl, or        C₂₋₉heteroaryl; or        -   two R⁶ substituents are taken together with the nitrogen            atom to which they are attached to form a 5- or 6-membered            heterocycle;    -   R⁷ is —H, halogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆ alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, or        —C₁₋₆alkyl-C₂₋₉heteroaryl; and    -   n is 0, 1, 2, 3, 4, or 5.

In some embodiments, for a compound of Formula (IV), Ring A isC₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, or 6- to10-membered aryl. In some embodiments, for a compound of Formula (IV),Ring A is 6- to 10-membered aryl. In some embodiments, for a compound ofFormula (IV), Ring A is phenyl. In some embodiments, for a compound ofFormula (IV), Ring A is naphthyl.

In some embodiments, for a compound of Formula (IV), Y is a bond, —O—,—S—, —C(R⁵)₂—, —NR⁶—, —NR⁶C(O)—, —C(O)NR⁶—, or —NR⁶C(O)NR⁶—. In someembodiments, for a compound of Formula (IV), Y is a bond or —C(R⁵)₂—. Insome embodiments, for a compound of Formula (IV), Y is a bond. In someembodiments, for a compound of Formula (IV), Y is —CH₂—.

In some embodiments, for a compound of Formula (IV), R¹ is —H, halogen,—OH, —CN, —N(R⁶)₂, —NR⁶C(O)R⁵, —C(O)OR⁵, —C(O)N(R⁶)₂, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, —C₁₋₆alkyl-OH,—C₁₋₆alkyl-OR⁵, —Cl₆alkyl-N(R⁶)₂, —O—C₁₋₆alkyl, —O—C₁₋₆alkyl-OH,—O—C₁₋₆alkyl-OR⁵, —O—C₁₋₆alkyl-N(R⁶)₂, or —S(═O)₂R⁵. In someembodiments, for a compound of Formula (IV), R¹ is —H, halogen, orC₁₋₆alkyl. In some embodiments, for a compound of Formula (IV), R¹ is—H, —Cl, or CH₃. In some embodiments, for a compound of Formula (IV), R¹is —H. In some embodiments, for a compound of Formula (IV), R¹ is —Cl.In some embodiments, for a compound of Formula (IV), R¹ is —CH₃.

In some embodiments, for a compound of Formula (IV), R² is —H, halogen,—NO₂, —CN, —OH, —OR⁵, —SR⁵, —N(R⁶)₂, —S(O)R⁵, —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵,—S(═O)₂N(R⁶)₂, —C(O)R⁵, —C(O)OR⁵, —OC(O)R⁵, —C(O)N(R⁶)₂, —OC(O)N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁵, —NR⁶C(O)OR⁵, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆heteroalkyl, —O—C₁₋₆alkyl,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, 6- to 10-memberedaryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more R⁷. In some embodiments, for a compound ofFormula (IV), R² is —H or —NR⁶C(O)R⁵. In some embodiments, for acompound of Formula (IV), R² is —H or —NR⁶C(O)C₂₋₉heteroaryl. In someembodiments, for a compound of Formula (IV), R² is —H. In someembodiments, for a compound of Formula (IV), R² is —NHC(O)pyridyl.

In some embodiments, for a compound of Formula (IV), n is 1, 2, or 3. Insome embodiments, for a compound of Formula (IV), n is 1 or 2. In someembodiments, for a compound of Formula (IV), n is 1. In someembodiments, for a compound of Formula (IV), n is 2. In someembodiments, for a compound of Formula (IV), n is 3.

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (IVa) or a pharmaceutically acceptable salt orisotopic variant thereof:

-   -   wherein    -   R¹ is halogen or C₁₋₆alkyl.

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (IVb) or a pharmaceutically acceptable salt orisotopic variant thereof:

-   -   wherein Y is a bond or —Cl₃alkyl-.

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (IVb) or a pharmaceutically acceptable salt orisotopic variant thereof:

-   -   wherein    -   Y is a bond or —CH₂—.

In some embodiments a compound of Formula (IV) or a pharmaceuticallyacceptable salt or isotopic variant thereof has the structure of:

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (V) or a pharmaceutically acceptable salt orisotopic variant thereof:

-   -   wherein    -   X¹ and X² are independently N or CR⁴;    -   Y is S, O, or NR¹;    -   R¹ is —H, —S(═O)₂R⁵, —S(═O)₂N(R⁶)₂, —C(O)R⁵, —C(O)OR⁵,        —C(O)N(R⁶)₂, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,        C₁₋₆heteroalkyl, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, or 6- to 10-membered aryl, wherein each alkyl,        haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and        heteroaryl is optionally substituted with one or more R⁷;    -   R² is —H, halogen, —NO₂, —CN, —OH, —OR⁵, —SR⁵, —N(R⁶)₂, —S(O)R⁵,        —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵, —S(═O)₂N(R⁶)₂, —C(O)R⁵, —C(O)OR⁵,        —OC(O)R⁵, —C(O)N(R⁶)₂, —OC(O)N(R⁶)₂, —NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁵,        —NR⁶C(O)OR⁵, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,        C₁₋₆heteroalkyl, —O—C₁₋₆alkyl, C₃₋₈cycloalkyl,        C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, 6- to 10-membered aryl, or        —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally        substituted with one or more R⁷; or    -   R¹ and R² are taken together with the atoms to which they are        attached to form an optionally substituted C₃₋₈heterocycloalkyl;        and    -   R³ and R⁴ are independently —H, halogen, —NO₂, —CN, —OH, —OR⁵,        —SR⁵, —N(R⁶)₂, —S(O)R⁵, —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵, —S(═O)₂N(R⁶)₂,        —C(O)R⁵, —C(O)OR⁵, —OC(O)R⁵, —C(O)N(R⁶)₂, —OC(O)N(R⁶)₂,        —NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁵, —NR⁶C(O)OR⁵, C₁₋₆ alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆heteroalkyl,        —O—C₁₋₆alkyl, C₃₋₈ cycloalkyl, C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, 6- to 10-membered aryl, or —O— phenyl, wherein        each alkyl, haloalkyl, heteroalkyl, cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl is optionally substituted        with one or more R⁷;    -   R⁵ is —H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, or        —C₁₋₆alkyl-C₂₋₉heteroaryl;    -   each R⁶ is independently —H, C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl,        —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl, —C₁₋₆alkyl-phenyl, or        C₂₋₉heteroaryl; or        -   two R⁶ substituents are taken together with the nitrogen            atom to which they are attached to form a 5- or 6-membered            heterocycle; and    -   R⁷ is —H, halogen, —S(═O)CH₃, —N(R⁶)₂, —C(O)N(R⁶)₂, C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆heteroalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl, —C₁₋₆        alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, or        —C₁₋₆alkyl-C₂₋₉heteroaryl.

In some embodiments, for a compound of Formula (V), X¹ and X² areindependently N or CR⁴. In some embodiments, for a compound of Formula(V), X¹ is N. In some embodiments, for a compound of Formula (V), X¹ isCR⁴. In some embodiments, for a compound of Formula (V), X² is N. Insome embodiments, for a compound of Formula (V), X² is CR⁴. In someembodiments, for a compound of Formula (V), X¹ is N and X² is CR⁴. Insome embodiments, for a compound of Formula (V), X¹ is CR⁴ and X² is N.

In some embodiments, for a compound of Formula (V), Y is S, O, or NR¹.In some embodiments, for a compound of Formula (V), Y is S. In someembodiments, for a compound of Formula (V), Y is NH. In someembodiments, for a compound of Formula (V), Y is NR¹.

In some embodiments, for a compound of Formula (V), R¹ is —H, —S(═O)₂R⁵,—S(═O)₂N(R⁶)₂, —C(O)R⁵, —C(O)OR⁵, —C(O)N(R⁶)₂, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₁₋₆heteroalkyl, C₃₋₈cycloalkyl,C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, or 6- to 10-membered aryl, whereineach alkyl, haloalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,and heteroaryl is optionally substituted with one or more R⁷. In someembodiments, for a compound of Formula (V), R¹ is —H, C₁₋₆alkyl,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, or 6- to10-membered aryl, wherein each cycloalkyl, heterocycloalkyl, aryl, andheteroaryl is optionally substituted with one or more R⁷. In someembodiments, for a compound of Formula (V), R¹ is aryl optionallysubstituted with one or more R⁷. In some embodiments, for a compound ofFormula (V), R¹ is 2,4-dichlorophenyl.

In some embodiments, for a compound of Formula (V), R² is —H, halogen,—NO₂, —CN, —OH, —OR⁵, —SR⁵, —N(R⁶)₂, —S(O)R⁵, —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵,—S(═O)₂N(R⁶)₂, —C(O)R⁵, —C(O)OR⁵, —OC(O)R⁵, —C(O)N(R⁶)₂, —OC(O)N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁵, —NR⁶C(O)OR⁵, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆heteroalkyl, —O—C₁₋₆alkyl,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, 6- to 10-memberedaryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more R⁷, or R¹ and R² are taken together withthe atoms to which they are attached to form an optionally substitutedC₃₋₈heterocycloalkyl. In some embodiments, for a compound of Formula(V), R² is —H, halogen, —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵, —S(═O)₂N(R⁶)₂, —C(O)R⁵,—C(O)OR⁵, —C(O)N(R⁶)₂, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, 6- to 10-memberedaryl, or —O-phenyl, wherein each alkyl, cycloalkyl, heterocycloalkyl,aryl, and heteroaryl is optionally substituted with one or more R⁷, orR¹ and R² are taken together with the atoms to which they are attachedto form an optionally substituted C₃₋₈heterocycloalkyl. In someembodiments, for a compound of Formula (V), R² is —C(O)N(R⁶)₂ or6-membered aryl optionally substituted with one or more R⁷. In someembodiments, for a compound of Formula (V), R² is 4-fluorophenyl. Insome embodiments, for a compound of Formula (V), R² is 4-chlorophenyl.In some embodiments, for a compound of Formula (V), R² is2-methylpyridinyl. In some embodiments, for a compound of Formula (V),R² is —C(O)NH-(2-methyl-6-chlorophenyl). In some embodiments, for acompound of Formula (V), R¹ and R² are taken together with the atoms towhich they are attached to form an optionally substitutedC₃₋₈heterocycloalkyl. In some embodiments, for a compound of Formula(V), R¹ and R² are taken together with the atoms to which they areattached to form a C₅ heterocycloalkyl.

In some embodiments, for a compound of Formula (V), R³ is —H, halogen,—NO₂, —CN, —OH, —OR⁵, —SR⁵, —N(R⁶)₂, —S(O)R⁵, —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵,—S(═O)₂N(R⁶)₂, —C(O)R⁵, —C(O)OR⁵, —OC(O)R⁵, —C(O)N(R⁶)₂, —OC(O)N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁵, —NR⁶C(O)OR⁵, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆heteroalkyl, —O—C₁₋₆alkyl,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, 6- to 10-memberedaryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more R⁷. In some embodiments, for a compound ofFormula (V), R³ is —H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆haloalkyl, C₁₋₆heteroalkyl, —O—C₁₋₆alkyl, C₃₋₈ cycloalkyl,C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, 6- to 10-membered aryl, or—O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is optionally substituted withone or more R⁷. In some embodiments, for a compound of Formula (V), R³is —H or C₂₋₉heteroaryl optionally substituted with one or more R⁷. Insome embodiments, for a compound of Formula (V), R³ is H. In someembodiments, for a compound of Formula (V), R³ is C₂₋₉heteroaryloptionally substituted with one or more R⁷. In some embodiments, for acompound of Formula (V), R³ is optionally substituted pyridinyl. In someembodiments, for a compound of Formula (V), R³ is optionally substitutedquinolinyl. In some embodiments, for a compound of Formula (V), R³ isoptionally substituted [1,2,4]triazolopyridinyl.

In some embodiments, for a compound of Formula (V), R⁴ is —H, halogen,—NO₂, —CN, —OH, —OR⁵, —SR⁵, —N(R⁶)₂, —S(O)R⁵, —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵,—S(═O)₂N(R⁶)₂, —C(O)R⁵, —C(O)OR⁵, —OC(O)R⁵, —C(O)N(R⁶)₂, —OC(O)N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁵, —NR⁶C(O)OR⁵, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, C₆heteroalkyl, —O—C₁₋₆alkyl, C₃₋₈cycloalkyl,C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, 6- to 10-membered aryl, or—O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl, cycloalkyl,heterocycloalkyl, aryl, and heteroaryl is optionally substituted withone or more R⁷. In some embodiments, for a compound of Formula (V), R⁴is —H, —N(R⁶)₂, —C(O)R⁵, —C(O)OR⁵, —OC(O)R⁵, —C(O)N(R⁶)₂, —OC(O)N(R⁶)₂,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆heteroalkyl,—O—C₁₋₆alkyl, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, 6-to 10-membered aryl, or —O-phenyl, wherein each alkyl, haloalkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isoptionally substituted with one or more R⁷. In some embodiments, for acompound of Formula (V), R⁴ is —N(R⁶)₂, C₁₋₆ alkyl, C₂₋₉heteroaryl, or6- to 10-membered aryl, wherein each aryl and heteroaryl is optionallysubstituted with one or more R⁷. In some embodiments, for a compound ofFormula (V), R⁴ is optionally substituted phenyl. In some embodiments,for a compound of Formula (V), R⁴ is optionally substituted pyridyl. Insome embodiments, for a compound of Formula (V), R⁴ is —NHpyrimidine. Insome embodiments, for a compound of Formula (V), R⁴ is —CH₂phenyl. Insome embodiments, for a compound of Formula (V), R⁴ is CH₂NHphenyl.

In some embodiments a compound of Formula (V) or a pharmaceuticallyacceptable salt or isotopic variant thereof has the structure of:

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (VI) or a pharmaceutically acceptable salt orisotopic variant thereof:

-   -   wherein    -   X¹ and X² are independently N or C;    -   X³ is N or CR⁴;    -   Y is a bond, —O—, —S—, —C(R⁵)₂, —NR⁶—, —NR⁶C(O)—, —C(O)NR⁶—, or        —NR⁶C(O)NR⁶—; R is —H, halogen, —NO₂, —CN, —OH, —OR⁵, —SR⁵,        —N(R⁶)₂, —S(O)R⁵, —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵, —S(═O)₂N(R⁶)₂,        —C(O)R⁵, —C(O)OR⁵, —OC(O)R⁵, —C(O)N(R⁶)₂, —OC(O)N(R⁶)₂,        —NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁵, —NR⁶C(O)OR⁵, C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆heteroalkyl, —O—C₁₋₆alkyl,        C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, 6- to        10-membered aryl, or —O-phenyl, wherein each alkyl, haloalkyl,        heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl        is optionally substituted with one or more R⁷;    -   R⁴ is —H, halogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆ alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, or        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein the alkyl, haloalkyl,        cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl are        optionally substituted;    -   R⁵ is —H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, or        —C₁₋₆alkyl-C₂₋₉heteroaryl;    -   each R⁶ is independently —H, C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl,        —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl, —C₁₋₆alkyl-phenyl, or        C₂₋₉heteroaryl; or        -   two R⁶ are taken together with the nitrogen atom to which            they are attached to form a 5- or 6-membered heterocycle;            and    -   R⁷ is —H, halogen, —S(═O)CH₃, —N(R⁶)₂, —C(O)N(R⁶)₂, C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆heteroalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, or        —C₁₋₆alkyl-C₂₋₉heteroaryl.

In some embodiments, for a compound of Formula (VII), X¹ and X² areindependently N or C. In some embodiments, for a compound of Formula(VII), X¹ is N. In some embodiments, for a compound of Formula (VII), X¹is C. In some embodiments, for a compound of Formula (VII), X² is N. Insome embodiments, for a compound of Formula (VII), X² is C. In someembodiments, for a compound of Formula (VII), X¹ is N and X² is C. Insome embodiments, for a compound of Formula (VII), X¹ is C and X² is N.

In some embodiments, for a compound of Formula (VII), X³ is N or CR⁴. Insome embodiments, for a compound of Formula (VII), X³ is N or CH. Insome embodiments, for a compound of Formula (VII), X³ is N. In someembodiments, for a compound of Formula (VII), X³ is CH.

In some embodiments, for a compound of Formula (VI), Y is a bond, —O—,—S—, —C(R⁵)₂, —NR⁶—, —NR⁶C(O)—, —C(O)NR⁶—, or —NR⁶C(O)NR⁶—. In someembodiments, for a compound of Formula (VI), Y is —O— or —NR⁶—. In someembodiments, for a compound of Formula (VI), Y is —O— or —NH—. In someembodiments, for a compound of Formula (VI), Y is —O—. In someembodiments, for a compound of Formula (VI), Y is —NH—.

In some embodiments, for a compound of Formula (VI), R is —H, halogen,—NO₂, —CN, —OH, —OR⁵, —SR⁵, —N(R⁶)₂, —S(O)R⁵, —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵,—S(═O)₂N(R⁶)₂, —C(O)R⁵, —C(O)OR⁵, —OC(O)R⁵, —C(O)N(R⁶)₂, —OC(O)N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁵, —NR⁶C(O)OR⁵, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆heteroalkyl, —O—C₁₋₆alkyl,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, 6- to 10-memberedaryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more R⁷. In some embodiments, for a compound ofFormula (VI), R is —H, halogen, —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵, —S(═O)₂N(R⁶)₂,—C(O)R⁵, —C(O)OR⁵, —OC(O)R⁵, —C(O)N(R⁶)₂, —OC(O)N(R⁶)₂, C₁₋₆alkyl,C₂₋₆alkenyl, C₁₋₆heteroalkyl, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,C₂₋₉heteroaryl, 6- to 10-membered aryl, or —O-phenyl, wherein eachalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroarylis optionally substituted with one or more R⁷. In some embodiments, fora compound of Formula (VI), R is —H or halogen. In some embodiments, fora compound of Formula (VI), R is —H. In some embodiments, for a compoundof Formula (VI), R is —Cl.

In some embodiments a compound of Formula (VI) or a pharmaceuticallyacceptable salt or isotopic variant thereof has the structure of:

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (V) or a pharmaceutically acceptable salt orisotopic variant thereof:

-   -   wherein    -   X¹ and X² are independently N or C;    -   X³ is N or CR⁴;    -   Y is a bond, —O—, —S—, —C(R⁵)₂, —NR⁶—, —NR⁶C(O)—, —C(O)NR⁶—, or        —NR⁶C(O)NR⁶—;    -   R¹ and R² are independently —H, halogen, —OH, —CN, —N(R⁶)₂,        —NR⁶C(O)R⁵, —C(O)OR⁵, —C(O)N(R⁶)₂, C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-OH, —C₁₋₆ alkyl-OR⁵,        —C₁₋₆alkyl-N(R⁶)₂, —O—C₁₋₆alkyl, —O—C₁₋₆alkyl-OH,        —O—C₁₋₆alkyl-OR⁵, —O—C₁₋₆alkyl-N(R⁶)₂, or —S(═O)₂R⁵;    -   R³ is —H, halogen, —NO₂, —CN, —OH, —OR⁵, —SR⁵, —N(R⁶)₂, —S(O)R⁵,        —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵, —S(═O)₂N(R⁶)₂, —C(O)R⁵, —C(O)OR⁵,        —OC(O)R⁵, —C(O)N(R⁶)₂, —OC(O)N(R⁶)₂, —NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁵,        —NR⁶C(O)OR⁵, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,        C₁₋₆heteroalkyl, —O—C₁₋₆alkyl, C₃₋₈cycloalkyl,        C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, 6- to 10-membered aryl, or        —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl,        cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally        substituted with one or more R⁷;    -   R⁴ is —H, halogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, or        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein the alkyl, haloalkyl,        cycloalkyl, phenyl, heteroaryl, and heterocycloalkyl are        optionally substituted;    -   R⁵ is —H, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, or        —C₁₋₆alkyl-C₂₋₉heteroaryl;    -   each R⁶ is independently —H, C₁₋₆alkyl, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl,        —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl, —C₁₋₆alkyl-phenyl, or        C₂₋₉heteroaryl; or        -   two R⁶ substituents are taken together with the nitrogen            atom to which they are attached to form a 5- or 6-membered            heterocycle;    -   R⁷ is —H, halogen, —S(═O)CH₃, —N(R⁶)₂, —C(O)N(R⁶)₂, C₁₋₆alkyl,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆heteroalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, or        —C₁₋₆alkyl-C₂₋₉heteroaryl; and    -   n is 0, 1, 2, 3, 4, or 5.

In some embodiments, for a compound of Formula (VII), X¹ and X² areindependently N or C. In some embodiments, for a compound of Formula(VII), X¹ is N. In some embodiments, for a compound of Formula (VII), X¹is C. In some embodiments, for a compound of Formula (VII), X² is N. Insome embodiments, for a compound of Formula (VII), X² is C. In someembodiments, for a compound of Formula (VII), X¹ is N and X² is C. Insome embodiments, for a compound of Formula (VII), X¹ is C and X² is N.

In some embodiments, for a compound of Formula (VII), X³ is N or CR⁴. Insome embodiments, for a compound of Formula (VII), X³ is N or CH. Insome embodiments, for a compound of Formula (VII), X³ is N. In someembodiments, for a compound of Formula (VII), X³ is CH.

In some embodiments, for a compound of Formula (VII), Y is a bond, —O—,—S—, —C(R⁵)₂, —NR⁶—, —NR⁶C(O)—, —C(O)NR⁶—, or —NR⁶C(O)NR⁶—. In someembodiments, for a compound of Formula (VII), Y is a bond, —NR⁶C(O)—, or—C(O)NR⁶—. In some embodiments, for a compound of Formula (VII), Y is abond, —NHC(O)—, or —C(O)NH—. In some embodiments, for a compound ofFormula (VII), Y is a bond. In some embodiments, for a compound ofFormula (VII), Y is —NHC(O)—. In some embodiments, for a compound ofFormula (VII), Y is —C(O)NH—.

In some embodiments, for a compound of Formula (VII), R¹ is —H, halogen,—OH, —CN, —N(R⁶)₂, —NR⁶C(O)R⁵, —C(O)OR⁵, —C(O)N(R⁶)₂, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, —C₁₋₆alkyl-OH,—C₁₋₆alkyl-OR⁵, —C₁₋₆alkyl-N(R⁶)₂, —O—C₁₋₆alkyl, —O—C₁₋₆alkyl-OH,—O—C₁₋₆alkyl-OR⁵, —O—C₁₋₆alkyl-N(R⁶)₂, or —S(═O)₂R⁵. In someembodiments, for a compound of Formula (VII), R¹ is —H, halogen,—N(R⁶)₂, —NR⁶C(O)R⁵, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-OH,—C₁₋₆alkyl-OR⁵, —C₁₋₆alkyl-N(R⁶)₂, —O—C₁₋₆alkyl-N(R⁶)₂, or —S(═O)₂R⁵. Insome embodiments, for a compound of Formula (VII), R¹ is —H or—S(═O)₂R⁵. In some embodiments, for a compound of Formula (VII), R¹ is—H. In some embodiments, for a compound of Formula (VII), R¹ is—S(═O)₂iso-propyl. In some embodiments, for a compound of Formula (VII),R¹ is —S(═O)₂tert-butyl.

In some embodiments, for a compound of Formula (VII), R² is —H, halogen,—OH, —CN, —N(R⁶)₂, —NR⁶C(O)R⁵, —C(O)OR⁵, —C(O)N(R⁶)₂, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, —C₁₋₆alkyl-OH,—C₁₋₆alkyl-OR⁵, —C₁₋₆alkyl-N(R⁶)₂, —O—C₁₋₆alkyl, —O—C₁₋₆alkyl-OH,—O—C₁₋₆alkyl-OR⁵, —O—C₁₋₆alkyl-N(R⁶)₂, or —S(═O)₂R⁵. In someembodiments, for a compound of Formula (VII), R² is —H, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₈cycloalkyl, —O—C₁₋₆alkyl, —O—C₁₋₆alkyl-OH, or —O—C₁₋₆alkyl-OR⁵. In some embodiments, for a compound ofFormula (VII), R² is —H or —O—C₁₋₆alkyl. In some embodiments, for acompound of Formula (VII), R² is —H. In some embodiments, for a compoundof Formula (VII), R² is —OCH₃. In some embodiments, for a compound ofFormula (VII), R² is —OCH₂CH₃.

In some embodiments, for a compound of Formula (VII), R³ is —H, halogen,—NO₂, —CN, —OH, —OR⁵, —SR⁵, —N(R⁶)₂, —S(O)R⁵, —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵,—S(═O)₂N(R⁶)₂, —C(O)R⁵, —C(O)OR⁵, —OC(O)R⁵, —C(O)N(R⁶)₂, —OC(O)N(R⁶)₂,—NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁵, —NR⁶C(O)OR⁵, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₁₋₆haloalkyl, C₁₋₆heteroalkyl, —O—C₁₋₆alkyl,C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, 6- to 10-memberedaryl, or —O-phenyl, wherein each alkyl, haloalkyl, heteroalkyl,cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionallysubstituted with one or more R⁷. In some embodiments, for a compound ofFormula (VII), R³ is —H, halogen, —N(R⁶)₂, —S(═O)₂R⁵, —NR⁶S(═O)₂R⁵,—S(═O)₂N(R⁶)₂, —NR⁶C(O)N(R⁶)₂, —NR⁶C(O)R⁵, —NR⁶C(O)OR⁵, C₁₋₆alkyl,C₁₋₆heteroalkyl, —O—C₁₋₆alkyl, C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,C₂₋₉heteroaryl, or 6- to 10-membered aryl, wherein each alkyl,heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl isoptionally substituted with one or more R⁷. In some embodiments, for acompound of Formula (VII), R³ is —H, halogen, —N(R⁶)₂, or C₁₋₆ alkyl. Insome embodiments, for a compound of Formula (VII), R³ is —H. In someembodiments, for a compound of Formula (VII), R³ is —Cl. In someembodiments, for a compound of Formula (VII), R³ is —F. In someembodiments, for a compound of Formula (VII), R³ is —CH₃.

In some embodiments a compound of Formula (VII) or a pharmaceuticallyacceptable salt or isotopic variant thereof has the structure of:

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (VIII) or a pharmaceutically acceptable salt orisotopic variant thereof:

-   -   wherein:    -   HET is or;

-   -   X is N and Y is CH; or        -   X is CH and Y is N;    -   R¹ is —H, or —F;    -   R² is C₁₋₃alkyl, —Cl, or —F;    -   R³ and R⁴ are each independently —H; —OR⁵;        —O—C₁₋₆alkyl-O—C₁₋₃alkyl; —O—C₃₋₆cycloalkyl; —C(O)R⁵, C₁₋₆alkyl        optionally substituted with one to three —OH, —F, C₃₋₈        heterocycloalkyl optionally substituted with oxo,        C₃₋₆cycloalkyl, —C(O)OR⁵, —O—C₁₋₆ alkyl, aryl, —N(R⁵)(R⁶), —CN,        or —C(O)N(R⁵)(R⁶); C₃₋₆cycloalkyl optionally substituted with        one to three —OH, one to three —F, C₁₋₆alkyl, —O—C₁₋₆alkyl,        C₁₋₆alkyl-OC₁₋₆alkyl, C₁₋₆alkyl-OH, —CF₃, —CN, —OC₃₋₆cycloalkyl,        —C(O)OH, —C(O)OR⁵, C₃₋₆ cycloalkyl, 5-6 membered heteroaryl,        C₃₋₆ heterocycloalkyl, N(R⁵)(R⁶), or —C(O)N(R⁵)(R⁶); —C(O)OR⁵;        —C(O)N(R⁵)(R⁶); —S(═O)₂N(R⁵)(R⁶); —S(O)_(n)—R⁵; a 4-10 membered        monocyclic, bicyclic, or spirocyclic heterocyclyl group        containing nitrogen, sulfur, or oxygen and optionally        substituted with one to three —N(R⁵)(R⁶), halogen, —C₁₋₆alkyl,        —O—C₁₋₆alkyl, or —C₁₋₆haloalkyl; aryl; —N(R⁵)(R⁶); or halogen;    -   R⁵ and R⁶ are each independently —H;        —C₁₋₆alkyl-C₃₋₈heterocycloalkyl; a 4-6 membered heterocycloalkyl        wherein the heterocycloalkyl ring is optionally substituted with        one to three C₁₋₆alkyl, —OC₁₋₆alkyl, —C₁₋₆haloalkyl,        C₁₋₆cycloalkyl, halogen, acyl, heterocycloalkyl,        heterocycloalkyl-C₁₋₆alkyl, heterocycloalkyl-O—C₁₋₆alkyl,        heterocycloalkyl-OH, heterocycloalkyl-C(O)CH₃,        heterocycloalkyl-C(O)OC₁₋₃alkyl, —C₁₋₆alkyl-heterocycloalkyl,        —C₁₋₆alkyl-heterocycloalkyl-C₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆        alkyl-O—C₁₋₆alkyl, C₃₋₆cycloalkyl, —C₁₋₆alkyl-cycloalkyl,        C₃₋₆cycloalkyl-C₁₋₆alkyl, C₃₋₆ cycloalkyl-O—C₁₋₆alkyl, or        C₃₋₆cycloalkyl-O—C₁₋₆alkyl-OH; acyl;        C₃₋₆cycloalkyl-C(O)—C₁₋₃alkyl; —C(O)—C₁₋₃alkyl-O—CH₃;        —C(O)—C₁₋₃alkyl; —C(O)—C₃₋₆cycloalkyl; —C(O)—NH—C₁₋₃alkyl;        —C(O)—NH—C₁₋₃alkyl; —C(O)—NH—C₃₋₆cycloalkyl optionally        monosubstituted or disubstituted with —C₁₋₃alkyl-OH,        —C(O)—NH—C₃₋₆heterocyclyl, —C(O)-aryl, —C(O)-heteroaryl, or        —S(O)_(n)—C₁₋₃alkyl; and C₁₋₆alkyl optionally substituted with        —OH, O—C₁₋₃alkyl, C₃₋₆cycloalkyl, heterocyclyl, aryl,        —NH—C₁₋₃alkyl, or —N—(C₁₋₃ alkyl)₂; or        -   R⁵ and R⁶ together with the nitrogen atom to which they are            attached form a 5-6 membered heterocyclic ring optionally            substituted with methyl; and    -   n is 0, 1, or 2.

In some embodiments, for a compound of Formula (VIII), HET is

X is N, Y is CH, and n is 1 or 2. In some embodiments, for a compound ofFormula (VIII), HET is

X is N, Y is CH, R² is —CH₃ or —Cl, R⁴ is H, and n is 2. In someembodiments, for a compound of Formula (VIII), HET is

X is N, Y is CH, R² is —CH₃ or —Cl, and n is 2. In some embodiments, fora compound of Formula (VIII), HET is

In some embodiments, for a compound of Formula (VIII), HET is

X is CH, Y is N, R² is —CH₃ or —Cl, and n is 2. In some embodiments, fora compound of Formula (VIII), HET is

X is CH, Y is N, R² is-CH₃ or —Cl, R⁴ is —H, and n is 2. In someembodiments, for a compound of Formula (VIII), HET is

X is CH, Y is N, R² is —CH₃ or —Cl, R⁴ is —H, and n is 2.

In some embodiments, for a compound of Formula (VIII), HET is

X is N, Y is CH, R¹ is —F, and R² is —CH₃. In some embodiments, for acompound of Formula (VIII), HET is

X is N, Y is CH, R¹ is —F, and R² is —CH₃. In some embodiments, for acompound of Formula (VIII), HET is

X is N, Y is CH, R¹ is —F, and R² is —CH₃.

In some embodiments, for a compound of Formula (VIII), HET is

X is N, Y is CH, R² is —CH₃ or —Cl, R⁴ is H, and n is 2. In someembodiments, for a compound of Formula (VIII), HET is

X is N, and Y is CH. In some embodiments, for a compound of Formula(VIII), HET is

X is CH, and Y is N. In some embodiments, for a compound of Formula(VIII), HET is

X is CH, and Y is N.

In the some embodiments for a compound of Formula (VIII), HET is

X is N, Y is CH, R² is —CH₃ or —Cl, R⁴ is H, and n is 2.

In some embodiments, a compound of Formula (VIII), or a pharmaceuticallyacceptable salt or isotopic variant thereof, has the structure of:

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (IX), or a pharmaceutically acceptable salt orisotopic variant thereof:

-   -   wherein    -   R is —H; or    -   R is

S(═O)₂CH₃

at one available ring position;

-   -   A and D are independently N or CH;    -   E is N, CH, or CR;    -   B and C are independently N, CH, or C—Cl;    -   R¹ is H; or    -   R¹ is C—Cl, C—F, C—OCH₃, C—C(CH₃)₃, or C—OH at one available        ring position; and    -   X—Y are C═C or

wherein R² is —H, C₁₋₆alkyl, C₁₋₆alkyl-OH, C₁₋₆alkyl-OC₁₋₆alkyl, orC₁₋₆alkyl-aryl.

In some embodiments, for a compound of Formula (IX), R² is methyl,ethyl, isobutyl, 2-hydroxyethyl, 2-methoxyethyl, benzyl, or phenethyl.In some embodiments, for a compound of Formula (IX), R² is methyl. Insome embodiments, for a compound of Formula (IX), R² is ethyl. In someembodiments, for a compound of Formula (IX), R² is isobutyl. In someembodiments, for a compound of Formula (IX), R² is 2-hydroxyethyl. Insome embodiments, for a compound of Formula (IX), R² is 2-methoxyethyl.In some embodiments, for a compound of Formula (IX), R² is benzyl. Insome embodiments, for a compound of Formula (IX), R² is phenethyl.

In some embodiments, a compound of Formula (IX), or a pharmaceuticallyacceptable salt and isotopic variant thereof, has the structure of:

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (IXa) or a pharmaceutically acceptable salt andisotopic variant thereof:

-   -   wherein    -   R is —H,

S(═O)₂CH₃, or;

-   -   R¹ is C₁₋₆alkyl or 6- to 10-membered aryl;    -   A and D are independently N or CH;    -   E is N, CH, or CR;    -   B and C are independently N, CH, or C—Cl;    -   R³ is H; or    -   R³ is C—Cl, C—F, C—OCH₃, C—C(CH₃)₃, or C—OH at one available        ring position; and    -   X—Y are C═C or

wherein R² is —H, C₁₋₆alkyl, C₁₋₆alkyl-OH, C₁₋₆alkyl-OC₁₋₆alkyl, orC₁₋₆alkyl-aryl.

In some embodiments, for a compound of Formula (IXa), R¹ is methyl,ethyl, or propyl. In some embodiments, for a compound of Formula (IXa),R¹ is methyl. In some embodiments, for a compound of Formula (IXa), R₁is ethyl. In some embodiments, for a compound of Formula (IXa), R¹ ispropyl.

In some embodiments, for a compound of Formula (IXa), R² is methyl,ethyl, isobutyl, 2-hydroxyethyl, 2-methoxyethyl, benzyl, or phenethyl.In some embodiments, for a compound of Formula (IXa), R² is methyl. Insome embodiments, for a compound of Formula (IXa), R² is ethyl. In someembodiments, for a compound of Formula (IXa), R² is isobutyl. In someembodiments, for a compound of Formula (IXa), R² is 2-hydroxyethyl. Insome embodiments, for a compound of Formula (IXa), R² is 2-methoxyethyl.In some embodiments, for a compound of Formula (IXa), R² is benzyl. Insome embodiments, for a compound of Formula (IXa), R² is phenethyl.

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (X), or a pharmaceutically acceptable salt orisotopic variant thereof:

-   -   wherein    -   Cy is C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, 6- to 10-membered        aryl, or C₂₋₉heteroaryl;    -   Y is absent, —CR^(b)R^(b)—, —O—, —NR^(b)—, or —S(O)_(n)—;    -   R¹ is C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl, 6- to 10-membered        aryl, or C₂₋₉heteroaryl, each of which is optionally substituted        with one to three R^(a);    -   R³ is —H, C₂₋₉heterocycloalkyl, or C₂₋₉heteroaryl, wherein the        heterocycloalkyl and heteroaryl are optionally substituted with        one to three —F, —Cl, —Br, I, —CN, —NO₂, —OR^(b), C₁₋₄alkyl,        —C₁₋₃alkyl-OR^(b), —C₁₋₃alkyl-NR^(b)R^(b), C₁₋₄haloalkyl,        C₁₋₄haloalkoxy, C₃₋₈ cycloalkyl, —NR^(b)R^(b), —C(O)NR^(b)R^(b),        —NR^(b)C(O)NR^(b)R^(b), —S(O)_(n)NR^(b)R^(b), C(O)OR^(b),        —OC(O)OR^(b), —S(O)_(n)R^(b), —NR^(b)S(O)_(n)R^(b), —C(S)OR^(b),        —OC(S)R^(b), —NR^(b)C(O)R^(b), —C(S)NR^(b)R^(b),        —NR^(b)C(S)R^(b), —NR^(b)C(O)OR^(b), —OC(O)NR^(b)R^(b),        —NR^(b)C(S)OR^(b), —OC(S)NR^(b)R^(b), —NRC(S)NR^(b)R^(b),        —C(S)R^(b), or —C(O)R^(b);    -   each R⁴ is independently halogen, —CN, —NR^(b)R^(b), —OR^(b),        C₁₋₄alkyl, —C₁₋₃alkyl-OR^(b), —C₁₋₃ alkyl-NR^(b)R^(b),        C₁₋₄haloalkyl, or C₁₋₄haloalkoxy;    -   each R^(a) is independently —F, —Cl, —Br, I, —CN, OR^(b),        C₁₋₄alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₄haloalkyl,        C₁₋₄haloalkoxy, —C₁₋₃alkyl-OR^(b), or —C₁₋₃alkyl-NR^(b)R^(b);        -   each R^(b) is independently —H or C₁₋₄alkyl;    -   x is 0, 1, 2, 3, or 4;    -   each m is independently 0, 1, 2, or 3; and    -   each n is independently 0, 1, or 2.

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (Xa) or a pharmaceutically acceptable salt orisotopic variant thereof:

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (Xb) or a pharmaceutically acceptable salt orisotopic variant thereof:

In some embodiments, for a compound of Formula (X), R¹ is optionallysubstituted phenyl, optionally substituted cyclopentyl, optionallysubstituted cyclohexyl, optionally substituted thienyl, optionallysubstituted pyridinyl, optionally substituted thiazolyl, optionallysubstituted pyrrolyl, optionally substituted imidazolyl, optionallysubstituted furanyl, optionally substituted oxazolyl, optionallysubstituted isoxazolyl, optionally substituted pyrazolyl, optionallysubstituted isothiazolyl, optionally substituted pyrmidinyl, optionallysubstituted pyrazinyl, optionally substituted pyridazinyl, optionallysubstituted oxadiazolyl, optionally substituted tetrahydropyranyl,optionally substituted triazolyl, or optionally substitutedthiadiazolyl. In some embodiments, for a compound of Formula (X), R¹ isoptionally substituted phenyl, optionally substituted cyclopentyl,optionally substituted thienyl, or optionally substitutedtetrahydropyranyl. In some embodiments, for a compound of Formula (X),R¹ is optionally substituted phenyl. In some embodiments, for a compoundof Formula (X), R¹ is optionally substituted cyclopentyl. In someembodiments, for a compound of Formula (X), R¹ is optionally substitutedthienyl. In some embodiments, for a compound of Formula (X), R¹ isoptionally substituted tetrahydropyranyl.

In some embodiments, for a compound of Formula (X), R³ is optionallysubstituted monocyclic heterocycloalkyl or optionally substitutedmonocyclic heteroaryl. In some embodiments, for a compound of Formula(X), R³ is optionally substituted monocyclic heterocycloalkyl. In someembodiments, for a compound of Formula (X), R³ is optionally substitutedmonocyclic heterocycloaryl.

In some embodiments, for a compound of Formula (X), m is 0 to 3. In someembodiments, for a compound of Formula (X), m is 0. In some embodiments,for a compound of Formula (X), m is 1. In some embodiments, for acompound of Formula (X), m is 2. In some embodiments, for a compound ofFormula (X), m is 3.

In some embodiments, for a compound of Formula (X), R³ is optionallysubstituted azetidinyl, optionally substituted morpholinyl, optionallysubstituted piperazinyl, optionally substituted piperidinyl, optionallysubstituted tetrahydropyranyl, optionally substituted pyrrolidinyl,optionally substituted thiomorpholinyl, optionally substitutedtetrahydrofuryanyl, optionally substituted homomorpholinyl, optionallysubstituted homopiperazinyl, optionally substituted thiomorpholinedioxide, or optionally substituted thienomorpholine oxide. In someembodiments, for a compound of Formula (X), R³ is optionally substitutedmorpholinyl, optionally substituted piperazinyl, optionally substitutedpiperidinyl, or optionally substituted thiomorpholinyl. In someembodiments, for a compound of Formula (X), R³ is optionally substitutedmorpholinyl. In some embodiments, for a compound of Formula (X), R³ isoptionally substituted piperazinyl. In some embodiments, for a compoundof Formula (X), R³ is optionally substituted piperidinyl. In someembodiments, for a compound of Formula (X), R³ is optionally substitutedthiomorpholinyl.

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (Xc) or a pharmaceutically acceptable salt orisotopic variant thereof:

-   -   wherein    -   R⁵ is C₁₋₄alkyl or —C₁₋₃alkyl-OR^(b).

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (Xd) or a pharmaceutically acceptable salt orisotopic variant thereof:

-   -   wherein:    -   Y is absent or —CH₂—; and    -   Y is attached to the meta or para position of the phenyl ring.

Disclosed herein, are antagonists or partial antagonists of RIPK2 havinga structure of Formula (Xe) or a pharmaceutically acceptable salt orisotopic variant thereof:

-   -   wherein    -   R⁵ is —H, C₁₋₄alkyl, or —C₁₋₃alkyl-OR^(b);    -   Y is absent or —CH₂—; and    -   Y is attached to the meta or para position of the phenyl ring.

In some embodiments, for a compound of Formula (X), R¹ is

In some embodiments, for a compound of Formula (X), R¹ is

wherein each R^(a) is independently —F, —Cl, or —CH₃.

Disclosed herein are additional therapeutic agents comprising amodulator of CD30 ligand (CD30L) (Entrez Gene ID: 943). In someembodiments, the modulator of CD30L is an agonist or an antagonist ofCD30L. In some instances, the antagonist of CD30L is an inhibitor ofCD30L. In some embodiments, an inhibitor of CD30L specifically bindsdirectly or indirectly to CD30L, CD30, or a molecule that interferesdirectly or indirectly with binding between CD30L and CD30. In someembodiments, as used herein, an inhibitor of CD30L comprises an agentthat modulates at least one functional activity of CD30L, such asbinding to CD30. Non-limiting examples of inhibitors of CD30L includeagents that specifically bind to CD30L, including a polypeptide such asan anti-CD30L antibody or antigen binding fragment thereof, and anucleic acid, e.g., an antisense construct, siRNA, and ribozyme. Anantisense construct includes an expression plasmid that when transcribedin the cell produces RNA complementary to a portion of mRNA encodingCD30L, and an oligonucleotide that inhibits protein expression byhybridizing with the CD30L mRNA. In some embodiments the inhibitor ofCD30L comprises a non-polypeptide or non-nucleic acid portion as anactive agent that binds to and inhibits CD30L activity.

In some embodiments, an inhibitor of CD30L is a polypeptide that bindsto CD30L and/or CD30. In some cases, the polypeptide is a CD30polypeptide or a portion thereof, wherein the portion retains theability to bind to CD30L. A portion of a CD30 polypeptide includes atleast about 10, 15, 20, 25, 30, 35, 40, 45, or 50 amino acids that haveat least about 85%, 90%, or 95% identity to human CD30 having SEQ ID NO:53, or SEQ ID NO: 54, or a sequence of any CD30 protein-coding isoform(for e.g., P28908). For example, an inhibitor of CD30L comprises a CD30polypeptide that comprises all or part of the extracellular region ofhuman CD30. In some embodiments, the CD30 polypeptide comprises aminoacids 19-390 of SEQ ID NO: 2018 or a binding fragment thereof, having atleast about 85%, 90%, or 95% sequence identity to CD30. In someembodiments, the CD30 polypeptide is a homologue of mammalian CD30,e.g., the CD30 polypeptide inhibitor of CD30L is a viral CD30polypeptide or fragment thereof. As a non-limiting example, the viralCD30 polypeptide comprises viral CD30 from a poxvirus, such asectromelia virus or cowpox virus.

In a non-limiting example, the inhibitor is an anti-CD30L antibody or ananti-CD30 antibody. As used herein, an antibody includes anantigen-binding fragment of a full length antibody, e.g., a Fab or scFv.In some embodiments, the antibody binds to the extracellular domain ofCD30L. In some embodiments, an anti-CD30L antibody comprises a heavychain comprising three complementarity-determining regions: HCDR1,HCDR2, and HCDR3; and a light chain comprising threecomplementarity-determining regions: LCDR1, LCDR2, and LCDR3. In someembodiments, the anti-CD30L antibody comprises a HCDR1 comprising SEQ IDNO: 20100, a HCDR2 comprising SEQ ID NO: 20101, a HCDR3 comprising SEQID NO: 20102, a LCDR1 comprising SEQ ID NO: 20103, a LCDR2 comprisingSEQ ID NO: 20104, and a LCDR3 comprising SEQ ID NO: 20105.

In some embodiments, the anti-CD30L antibody comprises a HCDR1comprising SEQ ID NO: 20106, a HCDR2 comprising SEQ ID NO: 20107, aHCDR3 comprising SEQ ID NO: 20108, a LCDR1 comprising SEQ ID NO: 20109,a LCDR2 comprising SEQ ID NO: 20110, and a LCDR3 comprising SEQ ID NO:20111.

In some embodiments, the anti-CD30L antibody comprises a HCDR1comprising SEQ ID NO: 20112, a HCDR2 comprising SEQ ID NO: 20113, aHCDR3 comprising SEQ ID NO: 20114, a LCDR1 comprising SEQ ID NO: 20115,a LCDR2 comprising SEQ ID NO: 20116, and a LCDR3 comprising SEQ ID NO:20117.

In some embodiments, the anti-CD30L antibody comprises a HCDR1comprising SEQ ID NO: 20118, a HCDR2 comprising SEQ ID NO: 20119, aHCDR3 comprising SEQ ID NO: 20120, a LCDR1 comprising SEQ ID NO: 20121,a LCDR2 comprising SEQ ID NO: 20122, and a LCDR3 comprising SEQ ID NO:20123.

In some embodiments, the anti-CD30L antibody comprises a HCDR1comprising SEQ ID NO: 20124, a HCDR2 comprising SEQ ID NO: 20125, aHCDR3 comprising SEQ ID NO: 20126, a LCDR1 comprising SEQ ID NO: 20127,a LCDR2 comprising SEQ ID NO: 20128, and a LCDR3 comprising SEQ ID NO:20129.

In some embodiments, the anti-CD30L antibody comprises a HCDR1comprising SEQ ID NO: 20130, a HCDR2 comprising SEQ ID NO: 20131, aHCDR3 comprising SEQ ID NO: 20132, a LCDR1 comprising SEQ ID NO: 20133,a LCDR2 comprising SEQ ID NO: 20134, and a LCDR3 comprising SEQ ID NO:20135.

In some cases, the anti-CD30L antibody comprises a heavy chain (HC)variable domain comprising SEQ ID NO: 20136 and a light chain (LC)variable domain comprising SEQ ID NO: 20137. In some cases, theanti-CD30L antibody comprises a heavy chain (HC) variable domaincomprising SEQ ID NO: 20138 and a light chain (LC) variable domaincomprising SEQ ID NO: 20139. In some cases, the anti-CD30L antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 20140and a light chain (LC) variable domain comprising SEQ ID NO: 20141. Insome cases, the anti-CD30L antibody comprises a heavy chain (HC)variable domain comprising SEQ ID NO: 20142 and a light chain (LC)variable domain comprising SEQ ID NO: 20143. In some cases, theanti-CD30L antibody comprises a heavy chain (HC) variable domaincomprising SEQ ID NO: 20144 and a light chain (LC) variable domaincomprising SEQ ID NO: 20145. In some cases, the anti-CD30L antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 20146and a light chain (LC) variable domain comprising SEQ ID NO: 20154. Insome cases, the anti-CD30L antibody comprises a heavy chain (HC)variable domain comprising SEQ ID NO: 20147 and a light chain (LC)variable domain comprising SEQ ID NO: 20154. In some cases, theanti-CD30L antibody comprises a heavy chain (HC) variable domaincomprising SEQ ID NO: 20148 and a light chain (LC) variable domaincomprising SEQ ID NO: 20154. In some cases, the anti-CD30L antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 20149and a light chain (LC) variable domain comprising SEQ ID NO: 20154. Insome cases, the anti-CD30L antibody comprises a heavy chain (HC)variable domain comprising SEQ ID NO: 20150 and a light chain (LC)variable domain comprising SEQ ID NO: 20154. In some cases, theanti-CD30L antibody comprises a heavy chain (HC) variable domaincomprising SEQ ID NO: 20151 and a light chain (LC) variable domaincomprising SEQ ID NO: 20154. In some cases, the anti-CD30L antibodycomprises a heavy chain (HC) variable domain comprising SEQ ID NO: 20152and a light chain (LC) variable domain comprising SEQ ID NO: 20154. Insome cases, the anti-CD30L antibody comprises a heavy chain (HC)variable domain comprising SEQ ID NO: 20153 and a light chain (LC)variable domain comprising SEQ ID NO: 20154.

In some embodiments, the anti-CD30 antibody comprises a heavy chainvariable region comprising SEQ ID NO: 55 and a light chain variableregion comprising SEQ ID NO: 56. Non-limiting examples of anti-CD30antibodies include MDX-60, Ber-H2, SGN-30 (cAC10), Ki-4.dgA, HRS-3/A9,AFM13, and H22xKi-4.

In some embodiments, the anti-CD30 antibody comprises an antibody drugconjugate. As a non-limiting example, the antibody drug conjugate isbrentuximab, an anti-CD30 antibody conjugated to monomethyl auristatinE.

TABLE 3 Exemplary CD30 Ligand Antibodies Antibody SEQ ID NO SequenceHCDR1 A1 20100 SYIWS HCDR2 A1 20101 RIYASGNTNYNPSLKS HCDR3 A1 20102DYRVAGTYYYYYGLDV LCDR1 A1 20103 TGTSSDVGVYDYVS LCDR2 A1 20104 EVSNRPSLCDR3 A1 20105 SSYTSRSTWV HCDR1 A2 20106 SYYWT HCDR2 A2 20107RIYTSGITNYNPSLKS HCDR3 A2 20108 ERVVGASRYYYYGVDV LCDR1 A2 20109TGTSSDVGLYNYVS LCDR2 A2 20110 EVNNRPS LCDR3 A2 20111 SSYTSSSTWV HCDR1 A320112 SYYWT HCDR2 A3 20113 RIYTSGITNYNPSLKS HCDR3 A3 20114ERVVGASRYYYYGVDV LCDR1 A3 20115 TGTSSDIGLYDYVS LCDR2 A3 20116 EVNNRPSLCDR3 A3 20117 SSYTSSSTWV HCDR1 A4 20118 SYSWS HCDR2 A4 20119RTSTSGRNNYNPSLKS HCDR3 A4 20120 DFTIAARRYYYYGMDV LCDR1 A4 20121TGTSSDIGLYNYVS LCDR2 A4 20122 EVINRPS LCDR3 A4 20123 SSYTSSSTWV HCDR1 A520124 NNYWS HCDR2 A5 20125 RVYSSGLTNYKPSLKS HCDR3 A5 20126ERATVTTRYHYDGMDV LCDR1 A5 20127 TGSSSDIGTYNYVS LCDR2 A5 20128 EVNNRPSLCDR3 A5 20129 SSYSSSSTWV HCDR1 A6 20130 SYYWS HCDR2 A6 20131RIFASGSTNYNPSLRS HCDR3 A6 20132 ERVGVQDYYHYSGMDV LCDR1 A6 20133TGTSSDVGLYNYVS LCDR2 A6 20134 EVSKRPS LCDR3 A6 20135 SSYTSSSTWV HC Var 120136 QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWTWIRQPAGKGLEWIGRIYTSGITNYNPSLKSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCARERVVGASRYYYYGVD VWGQGTTVTVSS LC Var 1 20137QSALTQPASVSGSPGQSITISCTGTSSDVGLYNYVSWYQQHPDKAPKLMIFEVNNRPSGVSNRFSGSNSGNTASLTISGLQAEDEADYYCSSYTSSSTWVFGGGTKLTVL HC Var 2 20138QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWTWIRQPAGKGLEWIGRIYTSGITNYNPSLKSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCARERVVGASRYYYYGVD VWGQGTTVTVSS LC Var 2 20139QSALTQPASVSGSPGQSITISCTGTSSDIGLYDYVSWYQQHPDRAPKLIIFEVNNRPSGVSYRFSGSNSGNTASLTIS GLQAEDEADYYCSSYTSSSTWVFGGGTKLTVLHC Var 3 20140 QVQLQESGPGLVKPSETLSLTCTVSGGSISSYSWSWIRQPAGKGLEWIGRTSTSGRNNYNPSLKSRVTMSVDTSKNQFSLKLNSVTAADTAVYYCARDFTIAARRYYYYGM DVWGQGTTVTVSS LC Var 3 20141QSALTQPASVSGSPGQSITISCTGTSSDIGLYNYVSWYQQHPGKAPKLIIYEVINRPSGVSNRFSGSESGNTASLTIS GLQAEDEANYYCSSYTSSSTWVFGGGTKLTVLHC Var 4 20142 QVQLQESGPRLVKPSETLSLTCTVSGGSITNNYWSWIRQPAGKGLEWIGRVYSSGLTNYKPSLKSRVTMSVDTSKNQFSLRLNSVTAADTAVYYCARERATVTTRYHYDGM DVWGQGTSVTVSS LC Var 4 20143QSALTQPASVSGSPGQSITISCTGSSSDIGTYNYVSWYQQYPGKAPELMIYEVNNRPSGVSDRFSGSTSGNTASLTI SGLQANDEADYYCSSYSSSSTWVFGGGTKLTVLHC Var 5 20144 QVQLQESGPGLVKPSETLSLTCTVSGGSISSYYWSWIRQPAGKGLEWIGRIFASGSTNYNPSLRSRVTMSRDTSKNQFSLKLSSVTAADTAVYYCAKERVGVQDYYHYSGMD VWGQGTTVTVSS LC Var 5 20145QSALTQPASVSGSPGQSITISCTGTSSDVGLYNYVSWYQQQPGKAPKLMIYEVSKRPSGVSNRFSGSTSGNTASLTISGLQADDEADYSCSSYTSSSTWVFGGGTKLTVL HC Var 6 20146QVQLQESGPGLVKPSETLSLTCTVSGGSISSYIWSWIRQPAGKGLEWIGRIYASGNTNYNPSLKSRVTISVDTSKNQFSLKLSSMTAADTAVYYCARDYRVAGTYYYYYGLDV WGQGTTVTVSS HC Var 7 20147QVQLQESGPGLVKPSETLSLTCTVSGGSISSYIWSWIRQPAGKGLEWIGRIYASGNTNYNPSLKSRVTMSVDTSKNQFSLKLSSMTAADTAVYYCARDYRVAGTYYYYYGLD VWGQGTTVTVSS HC Var 8 20148QVQLQESGPGLVKPSETLSLTCTVSGGSISSYIWSWIRQPAGKGLEWIGRIYASGNTNYNPSLKSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCARDYRVAGTYYYYYGLD VWGQGTTVTVSS HC Var 9 20149QVQLQESGPGLVKPSETLSLTCTVSGGSISSYIWSWIRQPAGKGLEWIGRIYASGQTNYNPSLKSRVTMSVDTSKNQFSLKLSSMTAADTAVYYCARDYRVAGTYYYYYGLD VWGQGTTVTVSS HC Var 10 20150QVQLQESGPGLVKPSETLSLTCTVSGGSISSYIWSWIRQPAGKGLEWIGRIYASGQTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDYRVAGTYYYYYGLDV WGQGTTVTVSS HC Var 11 20151QVQLQESGPGLVKPSETLSLTCTVSGGSISSYIWSWIRQPAGKGLEWIGRIYASGNTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDYRVAGTYYYYYGLDV WGQGTTVTVSS HC Var 12 20152QVQLQESGPGLVKPSETLSLTCTVSGGSISSYIWSWIRQPAGKGLEWIGRIYASGQTNYNPSLKSRVTISVDTSKNQFSLKLSSMTAADTAVYYCARDYRVAGTYYYYYGLDV WGQGTTVTVSS HC Var 13 20153QVQLQESGPGLVKPSETLSLTCTVSGGSISSYIWSWIRQPAGKGLEWIGRIYASGQTNYNPSLKSRVTMSVDTSKNQFSLKLSSVTAADTAVYYCARDYRVAGTYYYYYGLD VWGQGTTVTVSS LC Var 6-13 20154QSALTQPASVSGSPGQSITISCTGTSSDVGVYDYVSWYQQHPGKAPKLMIYEVSNRPSGVSNRFSGSKSGNTASLTISGLQTEDEADYYCSSYTSRSTWVFGGGTKLTVL

Disclosed herein are additional therapeutic agents that are effective tomodify expression and/or activity of G-protein coupled receptor 35(GPR35) (Entrez Gene ID: 2859) (e.g., modulator of GPR35). Alternativelyor additionally, compositions, kits and methods disclosed herein maycomprise and/or utilize a therapeutic agent or use thereof, wherein thetherapeutic agent modifies expression and/or activity of a protein thatfunctions upstream or downstream of a pathway that involves GPR35. Insome embodiments, the modulator of GPR35 is effective to increase oractivate the activity or expression of GPR35 in the subject (e.g.,agonist or partial agonist). In some embodiments, the modulator of GPR35is effective to decrease or reduce the activity or expression of GPR35(e.g., antagonist or partial antagonist).

In some instances, the therapeutic agent is an antagonist of GPR35. Insome instances, the antagonist acts as an inverse agonist. Non-limitingexamples of inverse agonists are ML145 and ML144. In some instances, thetherapeutic agent is an allosteric modulator of GPR35. Methods disclosedherein may comprise administering the modulator of GPR35 alone. In otherinstances, methods disclosed herein may comprise administering themodulator of GPR35along with another therapeutic agent disclosed herein(e.g., anti-TL1A antibody), a nutritional-based therapy, a nature-basedtherapy, a diet-based therapy, or a combination thereof.

In some instances, the therapeutic agent is a small molecule drug. Byway of non-limiting example, a small molecule drug may be a chemicalcompound. In some cases, a small molecule has a molecular weight lessthan about 1,000 Da, or less than about 900 Da, or less than about 800Da. In some cases, a small molecule has a molecular weight from about 50Da to about 1,000 Da. In some instances, the therapeutic agent is alarge molecule drug. Large molecule drugs generally comprise a peptideor nucleic acid. By way of non-limiting example, the large molecule drugmay comprise an antibody or antigen binding antibody fragment. In someinstances, the therapeutic agent comprises a small molecule and a largemolecule. By way of non-limiting example, the therapeutic agent maycomprise an antibody-drug conjugate.

In some instances, the therapeutic agent is a small molecule that bindsGPR35. In some instances, the small molecule that binds GPR35 is a GPR35agonist. In some instances, the small molecule that binds GPR35 is aGPR35 partial agonist. In some instances, the small molecule that bindsGPR35 is a GPR35 antagonist. In some instances, the small molecule thatbinds GPR35 is a GPR35 partial agonist.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (I):

-   -   wherein:    -   X¹ and X² are independently selected from N and CR¹⁴;    -   R¹ is —CH₂R⁴, —CN, —B(OH)₂, —N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —C(O)OH,        —CH₂C(O)OH, —C(O)N(R¹⁰)₂, —C(O)NHS(O)₂N(R¹⁰)₂, —C₁₋₆alkyl-OH,        C₃₋₈cycloalkyl,

or a 5- or 6-membered heteroaryl optionally substituted with one, two,or three R¹ groups;

-   -   R² is H, —OH, —N(R¹⁰)₂, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂, —C(O)N(R¹⁰)₂,        OC(O)N(R¹⁰)₂, —O—C₁₋₆ alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹,        —C₁₋₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl,        C₃₋₈cycloalkyl;    -   each R³ is independently selected from halogen, —CN, —OH, —OR⁹,        —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂,        —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂—OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —Cl₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   R⁴ is

-   -   each R⁵ is independently selected from halogen, —CN, —OH, —OR⁹,        —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂,        —C(O)NHS(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂,        —OC(O)N(R¹⁰)₂—NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹,        C₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂,        —C₁₋₆alkyl-C(O)OR¹⁰, C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,        C₁₋₆haloalkyl-OH, C₃₋₈cycloalkyl, —C₁₋₆ alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl, and        C₁₋₉heteroaryl; wherein phenyl, —C₁₋₆alkyl-phenyl, and        C₁₋₉heteroaryl are optionally substituted with one, two, or        three groups independently selected from halogen, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and C₂₋₉heterocycloalkyl; and        wherein C₂₋₉heterocycloalkyl is optionally substituted with one,        two, or three groups independently selected from halogen,        C₁₋₆alkyl, C₁₋₆haloalkyl, and oxo;    -   R⁶ is —C(O)OR⁷, —C(O)NHS(O)₂N(R¹⁰)₂,

-   -   each R⁷ is independently selected from H and C₁₋₆alkyl;    -   each R⁸ is independently selected from halogen, —OH, —OR⁹,        —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂,        —C(O)NHS(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂,        —OC(O)N(R¹⁰)₂, —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆        alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂,        —C₁₋₆alkyl-C(O)OR¹⁰, C₁₋₆ haloalkyl, C₁₋₆haloalkyl-OH,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl, —C₁₋₆        alkyl-phenyl, C₂₋₉heterocycloalkyl, and C₁₋₉heteroaryl; wherein        phenyl, —C₁₋₆alkyl-phenyl, and C₁₋₉heteroaryl are optionally        substituted with one, two, or three groups independently        selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        and C₂₋₉heterocycloalkyl; and wherein C₂₋₉heterocycloalkyl is        optionally substituted with one, two, or three groups        independently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,        and oxo;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, —N(R¹¹)₂, and —C(O)OR¹²; or        two R¹⁰ and the nitrogen atom to which they are attached are        combined to form a 5- or 6-membered heterocycloalkyl ring        optionally substituted with one, two, or three groups        independently selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   R¹² is independently selected from H and C₁₋₆alkyl;    -   R¹³ is selected from H, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl;    -   each R¹⁴ is independently selected from C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl;    -   n is 0, 1, 2, or 3;    -   p is 0, 1, 2, 3, 4, or 5; and    -   q is 0, 1, 2, 3, or 4;    -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (II):

-   -   wherein:    -   X¹, X², Y¹, and Y² are independently selected from O, NR¹³, and        C(R¹⁴)₂;    -   R¹ and R² are independently selected from —S(O)R⁹, —S(O)₂R⁹,        —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹,        —C(O)N(R¹⁰)₂, —OC(O)N(R¹⁰)₂—NR¹⁰C(O)N(R¹⁰)₂—NR¹⁰C(O)R⁹,        —NR¹⁰C(O)OR⁹, C₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, and        —C₁₋₆alkyl-N(R¹⁰)₂;    -   R³ is selected from —OH, —OR⁹, —SR⁹, —N(R¹⁰)₂, —S(O)R⁹,        —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰,        —OC(O)R⁹, —C(O)N(R¹⁰)₂, —OC(O)N(R¹⁰), —NR¹⁰C(O)N(R¹⁰)₂,        —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl, —C₁₋₆alkyl-OH,        —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —C₁₋₆ alkyl-C₃-cycloalkyl;    -   each R⁴ and R⁵ is independently selected from halogen, —CN, —OH,        —OR⁹, —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹,        —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂,        —OC(O)N(R¹⁰)₂, —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆        alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl;    -   each R¹³ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆ alkyl-C₃cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl;    -   each R¹⁴ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆ alkyl-C₃-cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl;    -   m is 1, 2, 3, 4, or 5;    -   n is 1, 2, 3, 4, or 5;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, or 3;    -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (III):

-   -   wherein:    -   X¹ and X² are independently selected from O, NR¹³, and C(R¹⁴)₂;    -   R¹ and R² are independently selected from —S(O)R⁹, —S(O)₂R⁹,        —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹,        —C(O)N(R¹⁰)₂, —OC(O)N(R¹⁰)₂, —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹,        —NR¹⁰C(O)OR⁹, C₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, and        —C₁₋₆alkyl-N(R¹⁰)₂;    -   R³ and R⁴ are independently selected from H, halogen, —CN, —OH,        —OR⁹, —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹,        —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂,        —OC(O)N(R¹⁰)₂, —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆        alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —Cl₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl;    -   each R¹³ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆ alkyl-C₃-cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl; and    -   each R¹⁴ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆ alkyl-C₃cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl;        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (IV):

-   -   wherein:    -   X¹ and X² are independently selected from O, NR¹³, and C(R¹⁴)₂;    -   R¹ and R² are independently selected from —S(O)R⁹, —S(O)₂R⁹,        —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹,        —C(O)N(R¹⁰)₂, —OC(O)N(R¹⁰)₂—NR¹⁰C(O)N(R¹⁰)₂—NR¹⁰C(O)R⁹,        —NR¹⁰C(O)OR⁹, C₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, and        —C₁₋₆alkyl-N(R¹⁰)₂;    -   R³ and R⁴ are independently selected from H, halogen, —CN, —OH,        —OR⁹, —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹,        —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂,        —OC(O)N(R¹⁰)₂, —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆        alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl;    -   each R¹³ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆ alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl; and    -   each R¹⁴ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆ alkyl-C₃-cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl;        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (V):

-   -   wherein:    -   R¹ and R² are independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆ alkyl-C₃cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl;    -   each R³ is independently selected from halogen, —CN, —OH, —OR⁹,        —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂,        —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂, —OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆ alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl; and    -   p is 0, 1, 2, 3, or 4;        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (VI):

-   -   wherein:    -   X¹ and X² are independently selected from O, NR¹³, and C(R¹⁴)₂;    -   R¹ and R² are independently selected from —S(O)R⁹, —S(O)₂R⁹,        —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹,        —C(O)N(R¹⁰)₂, —OC(O)N(R¹⁰)₂—NR¹⁰C(O)N(R¹⁰)₂—NR¹⁰C(O)R⁹,        —NR¹⁰C(O)OR⁹, C₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, and        —C₁₋₆alkyl-N(R¹⁰)₂;    -   R³ and R⁴ are independently selected from H, halogen, —CN, —OH,        —OR⁹, —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹,        —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂,        —OC(O)N(R¹⁰)₂, —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆        alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl;    -   each R¹³ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆ alkyl-C₃-cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl; and    -   each R¹⁴ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆ alkyl-C₃cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl;        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (V):

-   -   wherein:    -   R¹ and R² are independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆ alkyl-C₃₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl;    -   each R³ is independently selected from halogen, —CN, —OH, —OR⁹,        —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂,        —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂, —OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —Cl₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl; and    -   p is 0, 1, 2, 3, or 4;        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (VII):

-   -   R¹ is selected from H, C₁₋₆alkyl, C₆haloalkyl, C₃₋₈cycloalkyl,        —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl, —C₁₋₆alkyl-phenyl, and        C₂₋₉heteroaryl;    -   R² is selected from H, halogen, —CN, —OH, —OR⁹, —SR⁹, —N(R¹⁰)₂,        —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂, —C(O)R⁹,        —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂—OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R³ and each R⁴ is independently selected from halogen, —CN,        —OH, —OR⁹, —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹,        —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂,        —OC(O)N(R¹⁰)₂—NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹,        C₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl;    -   p is 0, 1, 2, 3, or 4; and    -   q is 0, 1, 2, 3, or 4;        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (VIII):

-   -   wherein:    -   X is selected from —O—, —S—, and —SO₂—;    -   R¹ is selected from H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl, —C₁₋₆alkyl-phenyl, and        C₂₋₉heteroaryl;    -   each R² and each R³ is independently selected from halogen, —CN,        —OH, —OR⁹, —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹,        —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂,        —OC(O)N(R¹⁰)₂, —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹,        C₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —Cl₆alkyl-N(R¹⁰)₂,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   R⁴ is selected from —C(O)OH, —C(O)OR₁₀,

-   -   R⁵ is selected from H, halogen, —CN, —OH, —OR⁹, —SR⁹, —N(R¹⁰)₂,        —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂, —C(O)R⁹,        —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂—OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —Cl₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl;    -   p is 0, 1, 2, 3, or 4; and    -   q is 0, 1, 2, or 3;        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (IX):

-   -   wherein:    -   X is selected from —O— and —S—;    -   R¹ is selected from H, halogen, —CN, —OH, —OR⁹, —SR⁹, —N(R¹⁰)₂,        —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹)₂, —C(O)R⁹, —C(O)OR¹⁰,        —OC(O)R⁹, —C(O)N(R¹⁰)₂, —OC(O)N(R¹⁰)₂, —NR¹⁰C(O)N(R¹⁰)₂,        —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl, —C₁₋₆alkyl-OH,        —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl, C₂₋₆alkynyl,        C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   R² is selected from —C(O)OH, —C(O)OR¹⁰,

-   -   each R³ is independently selected from halogen, —CN, —OH, NO₂,        —OR⁹, —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹,        —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂,        —OC(O)N(R¹⁰)₂, —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆        alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl; and    -   p is 0, 1, 2, 3, or 4;        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (X):

-   -   wherein:    -   R¹ is selected from —C(O)OH, —C(O)OR¹⁰,

-   -   each R² is independently selected from halogen, —CN, —OH, —OR⁹,        —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂,        —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂—OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R³ is independently selected from H, halogen, —CN, —OH,        NO₂, —OR⁹, —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹,        —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂,        —OC(O)N(R¹⁰)₂, —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆        alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆ alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl; and    -   p is 0, 1, 2, 3, or 4;        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (XI):

-   -   wherein:    -   X is selected from —O—, —S—, and —SO₂—;    -   R¹ is selected from H, halogen, —CN, —OH, —OR⁹, —SR⁹, —N(R¹⁰)₂,        —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂, —C(O)R⁹,        —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂—OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —Cl₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R² and each R³ is independently selected from halogen, —CN,        —OH, —OR⁹, —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹,        —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂,        —OC(O)N(R¹⁰)₂—NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹,        C₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and        —C₁₋₆ alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl;    -   p is 0, 1, 2, 3, or 4; and    -   q is 0, 1, 2, 3, or 4;        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (XII):

-   -   wherein:    -   X is selected from —O—, —S—, —NR¹³—, and —C(R¹⁴)₂—;    -   each R¹ is independently selected from H, halogen, —CN, —OH,        —OR⁹, —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹,        —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂,        C₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   R² is selected from Hand C₁₋₆alkyl;    -   each R³ and each R⁴ is independently selected from halogen, —CN,        —OH, —OR⁹, —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹,        —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂,        —OC(O)N(R¹⁰)₂, NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹,        C₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl;    -   R¹³ is selected from H, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl;    -   R¹⁴ is selected from H, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl;    -   p is 0, 1, 2, 3, or 4; and    -   q is 0, 1, 2, 3, or 4;        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (XIII):

-   -   wherein:    -   X¹ and X² are independently —O—, —S—, or —NR¹³—;    -   R¹ is selected from —C(O)OH, —C(O)OR¹⁰,

-   -   R² is selected from H, halogen, —CN, —OH, —OR⁹, —SR⁹, —N(R¹⁰)₂,        —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂, —C(O)R⁹,        —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂, —OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R³ is independently selected from halogen, —CN, —OH, —OR⁹,        —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂,        —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂—OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl;    -   R¹³ is selected from H, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl; and    -   p is 0, 1 or 2;        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (XIV):

-   -   wherein:    -   R¹ and R² are independently selected from H, halogen, —CN, —OH,        —OR⁹, —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹,        —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹, —OC(O)R⁹, —C(O)N(R¹⁰)₂,        —OC(O)N(R¹⁰)₂, —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆        alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R³ is independently selected from halogen, —CN, —OH, —OR⁹,        —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂,        —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂—OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆ alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl; and    -   p is 0, 1, 2, 3, or 4;        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (XV):

-   -   wherein:    -   X is selected from —O—, —S—, and —SO₂—;    -   Y is N or CR²;    -   R¹ is —C(O)OH, —C(O)OR¹⁰,

-   -   each R² is independently selected from H, halogen, —CN, —OH,        —OR⁹, —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹,        —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂,        —OC(O)N(R¹⁰)₂, —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆        alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, and        —C₁₋₆ alkyl-C₃₋₈cycloalkyl;    -   each R³ is independently selected from halogen, —CN, —OH, —OR⁹,        —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂,        —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂, —OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —Cl₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl; and    -   p is 0, 1, 2, 3, or 4;        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (XVI):

-   -   wherein:    -   X is selected from —O—, —S—, and —NR¹³—;    -   R¹ is selected from —C(O)OH, —C(O)OR¹⁰,

-   -   each R² and each R⁷ is independently selected from halogen, —CN,        —OH, —OR⁹, —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹,        —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂,        —OC(O)N(R¹⁰)₂, —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹,        C₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   R³ and R⁴ are independently selected from H and C₁₋₆ alkyl;    -   R⁵ is selected from H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl, —C₁₋₆alkyl-phenyl, and        C₂₋₉heteroaryl;    -   R⁶ is independently H, halogen, —CN, —OH, —OR⁹, —SR⁹, —N(R¹⁰)₂,        —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂, —C(O)R⁹,        —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂—OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆ alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl;    -   R¹³ is selected from H, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, or 3;        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (XVII):

-   -   wherein:    -   X is selected from —O—, —S—, and —SO₂—;    -   R¹ is selected from —C(O)OH, —C(O)OR¹⁰,

-   -   each R² and each R³ is independently selected from halogen, —CN,        —OH, —OR⁹, —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹,        —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂,        —OC(O)N(R¹⁰)₂, —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹,        C₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl;    -   p is 0, 1, 2, or 3; and    -   q is 0, 1, 2, 3, or 4;        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (XVIII):

-   -   wherein:    -   R¹ is selected from —C(O)OH, —C(O)OR¹⁰,

-   -   R² is independently selected from H, halogen, —CN, —OH, —OR⁹,        —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂,        —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂, —OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R³ is independently selected from halogen, —CN, —OH, —OR⁹,        —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂,        —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂, —OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —Cl₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl; and    -   p is 0, 1, 2, 3, or 4;        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (XIX):

-   -   wherein:    -   X is selected from —O—, —S—, and —NR¹³—;    -   R¹ is selected from Hand C₁₋₆alkyl;    -   R² is independently selected from H, halogen, —CN, —OH, —OR⁹,        —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂,        —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂, —OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —Cl₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   R³ is selected from H, halogen, —CN, —OH, —OR⁹, —SR⁹, —N(R¹⁰)₂,        —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂, —C(O)R⁹,        —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂—OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl, —C₁₋₆        alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁴ is independently selected from halogen, —CN, —OH, —OR⁹,        —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂,        —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂—OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl, —C₁₋₆        alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆ alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆ alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl;    -   R¹³ is selected from H, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl; and    -   p is 0, 1, 2, 3, or 4;        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (XX):

-   -   wherein:    -   X is selected from —O— and —C(R¹⁴)₂—;    -   R¹ is selected from H, halogen, —CN, —OH, —OR⁹, —SR⁹, —N(R¹⁰)₂,        —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂, —C(O)R⁹,        —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂, —OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   R² is selected from H, halogen, —CN, —OH, —OR⁹, —SR⁹, —N(R¹⁰)₂,        —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂, —C(O)R⁹,        —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂—OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —Cl₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R³ and each R⁴ is selected from H, halogen, —CN, —OH, —OR⁹,        —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂,        —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂—OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl;    -   each R¹⁴ is independently selected from H, halogen, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl; and or a pharmaceutically acceptable        salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (XXI):

-   -   wherein:    -   X¹ and X² are independently selected from —O— and —S—;    -   each R¹ and each R² are independently selected from halogen,        —CN, —OH, —OR⁹, —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹,        —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂,        —OC(O)N(R¹⁰)₂, —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹,        C₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl;    -   R¹³ is selected from H, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl;    -   p is 0, 1, 2, or 3;    -   q is 0, 1, 2, or 3; and        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (XXII):

-   -   wherein:    -   X is selected from —O— and —S—;    -   R¹, R², and R³ are independently selected from H, halogen, —CN,        —OH, —OR⁹, —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹,        —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂,        —OC(O)N(R¹⁰)₂, —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆        alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁴ is selected from halogen, —CN, —OH, —OR⁹, —SR⁹,        —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂, —C(O)R⁹,        —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰), —OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —Cl₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl; and    -   p is 0, 1, 2, 3, or 4;        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (XXIII):

-   -   wherein:    -   each X is independently selected from —O— and —S—;    -   R¹ is selected from —C(O)OH, —C(O)OR¹⁰

-   -   each R² is selected from halogen, —CN, —OH, —OR⁹, —SR⁹,        —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂, —C(O)R⁹,        —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂—OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   R³ is selected from H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl, —C₁₋₆alkyl-phenyl, and        C₂₋₉heteroaryl;    -   each R⁴ and each R⁵ are independently selected from H, halogen,        —CN, —OH, —OR⁹, —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹,        —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂,        —OC(O)N(R¹⁰)₂—NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹,        C₁₋₆alkyl, —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   R⁶ is selected from C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and phenyl, wherein C₃₋₈cycloalkyl,        C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and phenyl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —Cl₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆ alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl; and    -   p is 0, 1, 2, 3, or 4;        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (XXIV):

-   -   wherein:    -   X is selected from —O— and —S—;    -   R¹ is selected from —C(O)OH, —C(O)OR¹⁰,

-   -   each R² is selected from H, halogen, —CN, —OH, —OR⁹, —SR⁹,        —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂, —C(O)R⁹,        —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂—OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —Cl₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R³ is selected from halogen, —CN, —OH, —OR⁹, —SR⁹,        —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂, —C(O)R⁹,        —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰), —OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —Cl₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   R⁴ is selected from H, C₁₋₆alkyl, C₁₋₆haloalkyl, and        C₃₋₈cycloalkyl;    -   R⁵ is selected from H, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        —C₁₋₆alkyl-C₃₋₈cycloalkyl, phenyl, —C₁₋₆alkyl-phenyl, and        C₂₋₉heteroaryl;    -   R⁶ is independently selected from H, C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl; and    -   p is 0, 1, 2, 3, or 4;        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (XXV):

-   -   wherein:    -   X is selected from CR² or N;    -   R¹ is selected from C₃₋₈cycloalkyl, C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and phenyl, wherein C₃₋₈cycloalkyl,        C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and phenyl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R² and each R⁶ is selected from halogen, —CN, —OH, —OR⁹,        —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂,        —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂—OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   R³ and R⁴ are independently selected from H, halogen, —CN, —OH,        —OR⁹, —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹,        —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂,        —OC(O)N(R¹⁰)₂, —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆        alkyl, —C₁₋₆alkyl-OH, —Cl₆alkyl-OR⁹, —Cl₆alkyl-N(R¹⁰)₂,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁵ are independently selected from H, halogen, —CN, —OH,        —OR⁹, —SR⁹, —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹,        —S(O)₂N(R¹⁰)₂, —C(O)R⁹, —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰)₂,        —OC(O)N(R¹⁰)₂, —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆        alkyl, —C₁₋₆alkyl-OH, —Cl₆alkyl-OR⁹, —C₁₋₆alkyl-N(R¹⁰)₂,        C₂₋₆alkenyl, C₂₋₆alkynyl, C₁₋₆ haloalkyl, C₃₋₈cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl;    -   p is 0, 1, 2, 3, 4, 5, or 6; and    -   q is 0, 1, 2, 3, or 4;        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is a compound ofFormula (XXVI):

-   -   wherein

-   -   R¹ is selected from —C(O)OH, —C(O)OR¹⁰,    -   each R² is selected from halogen, —CN, —OH, —OR⁹, —SR⁹,        —N(R¹⁰)₂, —S(O)R⁹, —S(O)₂R⁹, —NHS(O)₂R⁹, —S(O)₂N(R¹⁰)₂, —C(O)R⁹,        —C(O)OR¹⁰, —OC(O)R⁹, —C(O)N(R¹⁰), —OC(O)N(R¹⁰)₂,        —NR¹⁰C(O)N(R¹⁰)₂, —NR¹⁰C(O)R⁹, —NR¹⁰C(O)OR⁹, C₁₋₆alkyl,        —C₁₋₆alkyl-OH, —C₁₋₆alkyl-OR⁹, —Cl₆alkyl-N(R¹⁰)₂, C₂₋₆alkenyl,        C₂₋₆alkynyl, C₁₋₆haloalkyl, C₃₋₈ cycloalkyl, and        —C₁₋₆alkyl-C₃₋₈cycloalkyl;    -   each R⁹ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,        C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈ cycloalkyl, phenyl,        —C₁₋₆alkyl-phenyl, C₂₋₉heterocycloalkyl,        —C₁₋₆alkyl-C₂₋₉heterocycloalkyl, C₂₋₉heteroaryl, and        —C₁₋₆alkyl-C₂₋₉heteroaryl, wherein C₁₋₆alkyl, phenyl,        —C₁₋₆alkyl-phenyl, —C₁₋₆alkyl-C₂₋₉heterocycloalkyl,        C₂₋₉heteroaryl, and —C₁₋₆alkyl-C₂₋₉heteroaryl are optionally        substituted with one or two groups independently selected from        C₁₋₆alkyl, —OR¹¹, —N(R¹¹)₂, C₁₋₆alkyl, C₃₋₈cycloalkyl, —C(O)R¹²,        and —C(O)OR¹²;    -   each R¹⁰ is independently selected from H, C₁₋₆alkyl,        C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —C₁₋₆alkyl-C₃₋₈cycloalkyl,        phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl, wherein        C₁₋₆alkyl, phenyl, —C₁₋₆alkyl-phenyl, and C₂₋₉heteroaryl are        optionally substituted with one or two groups independently        selected from halogen, C₁₋₆alkyl, and —N(R¹¹)₂; or two R¹⁰ and        the nitrogen atom to which they are attached are combined to        form a 5- or 6-membered heterocycloalkyl ring optionally        substituted with one, two, or three groups independently        selected from C₁₋₆alkyl, oxo, and —C(O)OH;    -   each R¹¹ is independently selected from H and C₁₋₆alkyl;    -   each R¹² is independently selected from H and C₁₋₆alkyl;    -   p is 0, 1, 2, 3, or 4; and        -   or a pharmaceutically acceptable salt or solvate thereof.

In some instances, the small molecule that binds GPR35 is selected fromzaprinast, lodoxamide, bufrolin, TC-G 1001, nedocromil, PSB-13253,6-bromo-7-hydroxy-8-nitro-3-(1H-tetrazol-5-yl)-2H-chromen-2-one,6-bromo-7-hydroxy-8-nitro-2-oxo-2H-chromene-3-carboxylic acid,7-deshydroxypyrogallin-4-carboxylic acid (DCA), morin, cromolyn, T₃,reverse T₃, YE-210, cromoglicic acid, nedocromil, pamoic acid, andtyrphostin-51.

In some instances, the small molecule that binds GPR35 is selected frompamoic acid, amlexanox, furosemide, doxantrazole, kynurenic acid, DHICA,cyclic guanosine monophosphate (cGMP), 2,3,5-THB, ellagic acid, LPAspecies, and YE120.

In some instances, the small molecule that binds GPR35 is selected fromML-145, ML-194, and ML-144.

In some instances, the small molecule that binds GPR35 is selected from:

In some instances, the small molecule that binds GPR35 is selected from:

In some instances, the small molecule that binds GPR35 is selected from:

Pharmaceutical Composition

A pharmaceutical composition, as used herein, refers to a mixture of atherapeutic agent, with other chemical components (i.e. pharmaceuticallyacceptable inactive ingredients), such as carriers, excipients, binders,filling agents, suspending agents, flavoring agents, sweetening agents,disintegrating agents, dispersing agents, surfactants, lubricants,colorants, diluents, solubilizers, moistening agents, plasticizers,stabilizers, penetration enhancers, wetting agents, anti-foaming agents,antioxidants, preservatives, or one or more combination thereof.Optionally, the compositions include two or more therapeutic agent(e.g., one or more therapeutic agents and one or more additional agents)as discussed herein. In practicing the methods of treatment or useprovided herein, therapeutically effective amounts of therapeutic agentsdescribed herein are administered in a pharmaceutical composition to amammal having a disease, disorder, or condition to be treated, e.g., aninflammatory disease, fibrostenotic disease, and/or fibrotic disease. Insome embodiments, the mammal is a human. A therapeutically effectiveamount can vary widely depending on the severity of the disease, the ageand relative health of the subject, the potency of the therapeutic agentused and other factors. The therapeutic agents can be used singly or incombination with one or more therapeutic agents as components ofmixtures.

The pharmaceutical formulations described herein are administered to asubject by appropriate administration routes, including but not limitedto, intravenous, intraarterial, oral, parenteral, buccal, topical,transdermal, rectal, intramuscular, subcutaneous, intraosseous,transmucosal, inhalation, or intraperitoneal administration routes. Thepharmaceutical formulations described herein include, but are notlimited to, aqueous liquid dispersions, self-emulsifying dispersions,solid solutions, liposomal dispersions, aerosols, solid dosage forms,powders, immediate release formulations, controlled releaseformulations, fast melt formulations, tablets, capsules, pills, delayedrelease formulations, extended release formulations, pulsatile releaseformulations, multiparticulate formulations, and mixed immediate andcontrolled release formulations.

Pharmaceutical compositions including a therapeutic agent aremanufactured in a conventional manner, such as, by way of example only,by means of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

The pharmaceutical compositions may include at least a therapeutic agentas an active ingredient in free-acid or free-base form, or in apharmaceutically acceptable salt form. In addition, the methods andpharmaceutical compositions described herein include the use of N-oxides(if appropriate), crystalline forms, amorphous phases, as well as activemetabolites of these compounds having the same type of activity. In someembodiments, therapeutic agents exist in unsolvated form or in solvatedforms with pharmaceutically acceptable solvents such as water, ethanol,and the like. The solvated forms of the therapeutic agents are alsoconsidered to be disclosed herein.

In some embodiments, a therapeutic agent exists as a tautomer. Alltautomers are included within the scope of the agents presented herein.As such, it is to be understood that a therapeutic agent or a saltthereof may exhibit the phenomenon of tautomerism whereby two chemicalcompounds that are capable of facile interconversion by exchanging ahydrogen atom between two atoms, to either of which it forms a covalentbond. Since the tautomeric compounds exist in mobile equilibrium witheach other they may be regarded as different isomeric forms of the samecompound.

In some embodiments, a therapeutic agent exists as an enantiomer,diastereomer, or other stereoisomeric form. The agents disclosed hereininclude all enantiomeric, diastereomeric, and epimeric forms as well asmixtures thereof.

In some embodiments, therapeutic agents described herein may be preparedas prodrugs. A “prodrug” refers to an agent that is converted into theparent drug in vivo. Prodrugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent is not. The prodrug may also have improved solubility inpharmaceutical compositions over the parent drug. An example, withoutlimitation, of a prodrug would be a therapeutic agent described herein,which is administered as an ester (the “prodrug”) to facilitatetransmittal across a cell membrane where water solubility is detrimentalto mobility but which then is metabolically hydrolyzed to the carboxylicacid, the active entity, once inside the cell where water-solubility isbeneficial. A further example of a prodrug might be a short peptide(polyaminoacid) bonded to an acid group where the peptide is metabolizedto reveal the active moiety. In certain embodiments, upon in vivoadministration, a prodrug is chemically converted to the biologically,pharmaceutically or therapeutically active form of the therapeuticagent. In certain embodiments, a prodrug is enzymatically metabolized byone or more steps or processes to the biologically, pharmaceutically ortherapeutically active form of the therapeutic agent.

Prodrug forms of the therapeutic agents, wherein the prodrug ismetabolized in vivo to produce an agent as set forth herein are includedwithin the scope of the claims. Prodrug forms of the herein describedtherapeutic agents, wherein the prodrug is metabolized in vivo toproduce an agent as set forth herein are included within the scope ofthe claims. In some cases, some of the therapeutic agents describedherein may be a prodrug for another derivative or active compound. Insome embodiments described herein, hydrazones are metabolized in vivo toproduce a therapeutic agent.

In certain embodiments, compositions provided herein include one or morepreservatives to inhibit microbial activity. Suitable preservativesinclude mercury-containing substances such as merfen and thiomersal;stabilized chlorine dioxide; and quaternary ammonium compounds such asbenzalkonium chloride, cetyltrimethylammonium bromide andcetylpyridinium chloride.

In some embodiments, formulations described herein benefit fromantioxidants, metal chelating agents, thiol containing compounds andother general stabilizing agents. Examples of such stabilizing agents,include, but are not limited to: (a) about 0.5% to about 2% w/vglycerol, (b) about 0.1% to about 1% w/v methionine, (c) about 0.1% toabout 2% w/v monothioglycerol, (d) about 1 mM to about 10 mM EDTA, (e)about 0.01% to about 2% w/v ascorbic acid, (f) 0.003% to about 0.02% w/vpolysorbate 80, (g) 0.001% to about 0.05% w/v. polysorbate 20, (h)arginine, (i) heparin, (j) dextran sulfate, (k) cyclodextrins, (l)pentosan polysulfate and other heparinoids, (m) divalent cations such asmagnesium and zinc; or (n) combinations thereof.

The pharmaceutical compositions described herein are formulated into anysuitable dosage form, including but not limited to, aqueous oraldispersions, liquids, gels, syrups, elixirs, slurries, suspensions,solid oral dosage forms, aerosols, controlled release formulations, fastmelt formulations, effervescent formulations, lyophilized formulations,tablets, powders, pills, dragees, capsules, delayed releaseformulations, extended release formulations, pulsatile releaseformulations, multiparticulate formulations, and mixed immediate releaseand controlled release formulations. In one aspect, a therapeutic agentas discussed herein, e.g., therapeutic agent is formulated into apharmaceutical composition suitable for intramuscular, subcutaneous, orintravenous injection. In one aspect, formulations suitable forintramuscular, subcutaneous, or intravenous injection includephysiologically acceptable sterile aqueous or non-aqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and non-aqueous carriers, diluents,solvents, or vehicles include water, ethanol, polyols (propyleneglycol,polyethylene-glycol, glycerol, cremophor and the like), suitablemixtures thereof, vegetable oils (such as olive oil) and injectableorganic esters such as ethyl oleate. Proper fluidity can be maintained,for example, by the use of a coating such as lecithin, by themaintenance of the required particle size in the case of dispersions,and by the use of surfactants. In some embodiments, formulationssuitable for subcutaneous injection also contain additives such aspreserving, wetting, emulsifying, and dispensing agents. Prevention ofthe growth of microorganisms can be ensured by various antibacterial andantifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid,and the like. In some cases it is desirable to include isotonic agents,such as sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, such as aluminum monostearate and gelatin.

For intravenous injections or drips or infusions, a therapeutic agentdescribed herein is formulated in aqueous solutions, preferably inphysiologically compatible buffers such as Hank's solution, Ringer'ssolution, or physiological saline buffer. For transmucosaladministration, penetrants appropriate to the barrier to be permeatedare used in the formulation. Such penetrants are generally known in theart. For other parenteral injections, appropriate formulations includeaqueous or nonaqueous solutions, preferably with physiologicallycompatible buffers or excipients. Such excipients are known.

Parenteral injections may involve bolus injection or continuousinfusion. Formulations for injection may be presented in unit dosageform, e.g., in ampoules or in multi dose containers, with an addedpreservative. The pharmaceutical composition described herein may be ina form suitable for parenteral injection as a sterile suspensions,solutions or emulsions in oily or aqueous vehicles, and may containformulatory agents such as suspending, stabilizing and/or dispersingagents. In one aspect, the active ingredient is in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

For administration by inhalation, a therapeutic agent is formulated foruse as an aerosol, a mist or a powder. Pharmaceutical compositionsdescribed herein are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebulizer, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, such as, by way of example only, gelatin foruse in an inhaler or insufflator may be formulated containing a powdermix of the therapeutic agent described herein and a suitable powder basesuch as lactose or starch.

Representative intranasal formulations are described in, for example,U.S. Pat. Nos. 4,476,116, 5,116,817 and 6,391,452. Formulations thatinclude a therapeutic agent are prepared as solutions in saline,employing benzyl alcohol or other suitable preservatives, fluorocarbons,and/or other solubilizing or dispersing agents known in the art. See,for example, Ansel, H. C. et al., Pharmaceutical Dosage Forms and DrugDelivery Systems, Sixth Ed. (1995). Preferably these compositions andformulations are prepared with suitable nontoxic pharmaceuticallyacceptable ingredients. These ingredients are known to those skilled inthe preparation of nasal dosage forms and some of these can be found inREMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 21st edition, 2005. Thechoice of suitable carriers is dependent upon the exact nature of thenasal dosage form desired, e.g., solutions, suspensions, ointments, orgels. Nasal dosage forms generally contain large amounts of water inaddition to the active ingredient. Minor amounts of other ingredientssuch as pH adjusters, emulsifiers or dispersing agents, preservatives,surfactants, gelling agents, or buffering and other stabilizing andsolubilizing agents are optionally present. Preferably, the nasal dosageform should be isotonic with nasal secretions.

Pharmaceutical preparations for oral use are obtained by mixing one ormore solid excipient with one or more of the therapeutic agentsdescribed herein, optionally grinding the resulting mixture, andprocessing the mixture of granules, after adding suitable auxiliaries,if desired, to obtain tablets or dragee cores. Suitable excipientsinclude, for example, fillers such as sugars, including lactose,sucrose, mannitol, or sorbitol; cellulose preparations such as, forexample, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methylcellulose, microcrystalline cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or otherssuch as: polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. Ifdesired, disintegrating agents are added, such as the cross linkedcroscarmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or asalt thereof such as sodium alginate. In some embodiments, dyestuffs orpigments are added to the tablets or dragee coatings for identificationor to characterize different combinations of active therapeutic agentdoses.

In some embodiments, pharmaceutical formulations of a therapeutic agentare in the form of a capsules, including push fit capsules made ofgelatin, as well as soft, sealed capsules made of gelatin and aplasticizer, such as glycerol or sorbitol. The push fit capsules containthe active ingredients in admixture with filler such as lactose, binderssuch as starches, and/or lubricants such as talc or magnesium stearateand, optionally, stabilizers. In soft capsules, the active therapeuticagent is dissolved or suspended in suitable liquids, such as fatty oils,liquid paraffin, or liquid polyethylene glycols. In some embodiments,stabilizers are added. A capsule may be prepared, for example, byplacing the bulk blend of the formulation of the therapeutic agentinside of a capsule. In some embodiments, the formulations (non-aqueoussuspensions and solutions) are placed in a soft gelatin capsule. Inother embodiments, the formulations are placed in standard gelatincapsules or non-gelatin capsules such as capsules comprising HPMC. Inother embodiments, the formulation is placed in a sprinkle capsule,wherein the capsule is swallowed whole or the capsule is opened and thecontents sprinkled on food prior to eating.

All formulations for oral administration are in dosages suitable forsuch administration. In one aspect, solid oral dosage forms are preparedby mixing a therapeutic agent with one or more of the following:antioxidants, flavoring agents, and carrier materials such as binders,suspending agents, disintegration agents, filling agents, surfactants,solubilizers, stabilizers, lubricants, wetting agents, and diluents. Insome embodiments, the solid dosage forms disclosed herein are in theform of a tablet, (including a suspension tablet, a fast-melt tablet, abite-disintegration tablet, a rapid-disintegration tablet, aneffervescent tablet, or a caplet), a pill, a powder, a capsule, soliddispersion, solid solution, bioerodible dosage form, controlled releaseformulations, pulsatile release dosage forms, multiparticulate dosageforms, beads, pellets, granules. In other embodiments, thepharmaceutical formulation is in the form of a powder. Compressedtablets are solid dosage forms prepared by compacting the bulk blend ofthe formulations described above. In various embodiments, tablets willinclude one or more flavoring agents. In other embodiments, the tabletswill include a film surrounding the final compressed tablet. In someembodiments, the film coating can provide a delayed release of atherapeutic agent from the formulation. In other embodiments, the filmcoating aids in patient compliance (e.g., Opadry® coatings or sugarcoating). Film coatings including Opadry® typically range from about 1%to about 3% of the tablet weight. In some embodiments, solid dosageforms, e.g., tablets, effervescent tablets, and capsules, are preparedby mixing particles of a therapeutic agent with one or morepharmaceutical excipients to form a bulk blend composition. The bulkblend is readily subdivided into equally effective unit dosage forms,such as tablets, pills, and capsules. In some embodiments, theindividual unit dosages include film coatings. These formulations aremanufactured by conventional formulation techniques.

In another aspect, dosage forms include microencapsulated formulations.In some embodiments, one or more other compatible materials are presentin the microencapsulation material. Exemplary materials include, but arenot limited to, pH modifiers, erosion facilitators, anti-foaming agents,antioxidants, flavoring agents, and carrier materials such as binders,suspending agents, disintegration agents, filling agents, surfactants,solubilizers, stabilizers, lubricants, wetting agents, and diluents.Exemplary useful microencapsulation materials include, but are notlimited to, hydroxypropyl cellulose ethers (HPC) such as Klucel® orNisso HPC, low-substituted hydroxypropyl cellulose ethers (L-HPC),hydroxypropyl methyl cellulose ethers (HPMC) such as Seppifilm-LC,Pharmacoat®, Metolose SR, Methocel®-E, Opadry YS, PrimaFlo, BenecelMP824, and Benecel MP843, methylcellulose polymers such as Methocel®-A,hydroxypropylmethylcellulose acetate stearate Aqoat (HF-LS, HF-LG,HF-MS)and Metolose®, Ethylcelluloses (EC) and mixtures thereof such as E461,Ethocel®, Aqualon®-EC, Surelease®, Polyvinyl alcohol (PVA) such asOpadry AMB, hydroxyethylcelluloses such as Natrosol®,carboxymethylcelluloses and salts of carboxymethylcelluloses (CMC) suchas Aqualon®-CMC, polyvinyl alcohol and polyethylene glycol co-polymerssuch as Kollicoat IR®, monoglycerides (Myverol), triglycerides (KLX),polyethylene glycols, modified food starch, acrylic polymers andmixtures of acrylic polymers with cellulose ethers such as Eudragit®EPO, Eudragit® L30D-55, Eudragit® FS 30D Eudragit® L100-55, Eudragit®L100, Eudragit® 5100, Eudragit® RD100, Eudragit® E100, Eudragit® L12.5,Eudragit® S12.5, Eudragit® NE30D, and Eudragit® NE 40D, celluloseacetate phthalate, sepifilms such as mixtures of HPMC and stearic acid,cyclodextrins, and mixtures of these materials.

Liquid formulation dosage forms for oral administration are optionallyaqueous suspensions selected from the group including, but not limitedto, pharmaceutically acceptable aqueous oral dispersions, emulsions,solutions, elixirs, gels, and syrups. See, e.g., Singh et al.,Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002).In addition to therapeutic agent the liquid dosage forms optionallyinclude additives, such as: (a) disintegrating agents; (b) dispersingagents; (c) wetting agents; (d) at least one preservative, (e) viscosityenhancing agents, (f) at least one sweetening agent, and (g) at leastone flavoring agent. In some embodiments, the aqueous dispersionsfurther includes a crystal-forming inhibitor.

In some embodiments, the pharmaceutical formulations described hereinare self-emulsifying drug delivery systems (SEDDS). Emulsions aredispersions of one immiscible phase in another, usually in the form ofdroplets. Generally, emulsions are created by vigorous mechanicaldispersion. SEDDS, as opposed to emulsions or microemulsions,spontaneously form emulsions when added to an excess of water withoutany external mechanical dispersion or agitation. An advantage of SEDDSis that only gentle mixing is required to distribute the dropletsthroughout the solution. Additionally, water or the aqueous phase isoptionally added just prior to administration, which ensures stabilityof an unstable or hydrophobic active ingredient. Thus, the SEDDSprovides an effective delivery system for oral and parenteral deliveryof hydrophobic active ingredients. In some embodiments, SEDDS providesimprovements in the bioavailability of hydrophobic active ingredients.Methods of producing self-emulsifying dosage forms include, but are notlimited to, for example, U.S. Pat. Nos. 5,858,401, 6,667,048, and6,960,563.

Buccal formulations that include a therapeutic agent are administeredusing a variety of formulations known in the art. For example, suchformulations include, but are not limited to, U.S. Pat. Nos. 4,229,447,4,596,795, 4,755,386, and 5,739,136. In addition, the buccal dosageforms described herein can further include a bioerodible (hydrolysable)polymeric carrier that also serves to adhere the dosage form to thebuccal mucosa. For buccal or sublingual administration, the compositionsmay take the form of tablets, lozenges, or gels formulated in aconventional manner.

For intravenous injections, a therapeutic agent is optionally formulatedin aqueous solutions, preferably in physiologically compatible bufferssuch as Hank's solution, Ringer's solution, or physiological salinebuffer. For transmucosal administration, penetrants appropriate to thebarrier to be permeated are used in the formulation. For otherparenteral injections, appropriate formulations include aqueous ornonaqueous solutions, preferably with physiologically compatible buffersor excipients.

Parenteral injections optionally involve bolus injection or continuousinfusion. Formulations for injection are optionally presented in unitdosage form, e.g., in ampoules or in multi dose containers, with anadded preservative. In some embodiments, a pharmaceutical compositiondescribed herein is in a form suitable for parenteral injection as asterile suspensions, solutions or emulsions in oily or aqueous vehicles,and contain formulatory agents such as suspending, stabilizing and/ordispersing agents. Pharmaceutical formulations for parenteraladministration include aqueous solutions of an agent that modulates theactivity of a carotid body in water soluble form. Additionally,suspensions of an agent that modulates the activity of a carotid bodyare optionally prepared as appropriate, e.g., oily injectionsuspensions.

Conventional formulation techniques include, e.g., one or a combinationof methods: (1) dry mixing, (2) direct compression, (3) milling, (4) dryor non-aqueous granulation, (5) wet granulation, or (6) fusion. Othermethods include, e.g., spray drying, pan coating, melt granulation,granulation, fluidized bed spray drying or coating (e.g., wurstercoating), tangential coating, top spraying, tableting, extruding and thelike.

Suitable carriers for use in the solid dosage forms described hereininclude, but are not limited to, acacia, gelatin, colloidal silicondioxide, calcium glycerophosphate, calcium lactate, maltodextrin,glycerine, magnesium silicate, sodium caseinate, soy lecithin, sodiumchloride, tricalcium phosphate, dipotassium phosphate, sodium stearoyllactylate, carrageenan, monoglyceride, diglyceride, pregelatinizedstarch, hydroxypropylmethylcellulose, hydroxypropylmethylcelluloseacetate stearate, sucrose, microcrystalline cellulose, lactose, mannitoland the like.

Suitable filling agents for use in the solid dosage forms describedherein include, but are not limited to, lactose, calcium carbonate,calcium phosphate, dibasic calcium phosphate, calcium sulfate,microcrystalline cellulose, cellulose powder, dextrose, dextrates,dextran, starches, pregelatinized starch, hydroxypropylmethycellulose(HPMC), hydroxypropylmethycellulose phthalate,hydroxypropylmethylcellulose acetate stearate (HPMCAS), sucrose,xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethyleneglycol, and the like.

Suitable disintegrants for use in the solid dosage forms describedherein include, but are not limited to, natural starch such as cornstarch or potato starch, a pregelatinized starch, or sodium starchglycolate, a cellulose such as methylcrystalline cellulose,methylcellulose, microcrystalline cellulose, croscarmellose, or across-linked cellulose, such as cross-linked sodiumcarboxymethylcellulose, cross-linked carboxymethylcellulose, orcross-linked croscarmellose, a cross-linked starch such as sodium starchglycolate, a cross-linked polymer such as crospovidone, a cross-linkedpolyvinylpyrrolidone, alginate such as alginic acid or a salt of alginicacid such as sodium alginate, a gum such as agar, guar, locust bean,Karaya, pectin, or tragacanth, sodium starchglycolate, bentonite, sodiumlauryl sulfate, sodium lauryl sulfate in combination starch, and thelike.

Binders impart cohesiveness to solid oral dosage form formulations: forpowder filled capsule formulation, they aid in plug formation that canbe filled into soft or hard shell capsules and for tablet formulation,they ensure the tablet remaining intact after compression and helpassure blend uniformity prior to a compression or fill step. Materialssuitable for use as binders in the solid dosage forms described hereininclude, but are not limited to, carboxymethylcellulose,methylcellulose, hydroxypropylmethylcellulose,hydroxypropylmethylcellulose acetate stearate, hydroxyethylcellulose,hydroxypropylcellulose, ethylcellulose, and microcrystalline cellulose,microcrystalline dextrose, amylose, magnesium aluminum silicate,polysaccharide acids, bentonites, gelatin, polyvinylpyrrolidone/vinylacetate copolymer, crospovidone, povidone, starch, pregelatinizedstarch, tragacanth, dextrin, a sugar, such as sucrose, glucose,dextrose, molasses, mannitol, sorbitol, xylitol, lactose, a natural orsynthetic gum such as acacia, tragacanth, ghatti gum, mucilage of isapolhusks, starch, polyvinylpyrrolidone, larch arabogalactan, polyethyleneglycol, waxes, sodium alginate, and the like.

In general, binder levels of 20-70% are used in powder-filled gelatincapsule formulations. Binder usage level in tablet formulations varieswhether direct compression, wet granulation, roller compaction, or usageof other excipients such as fillers which itself can act as moderatebinder. Binder levels of up to 70% in tablet formulations is common.

Suitable lubricants or glidants for use in the solid dosage formsdescribed herein include, but are not limited to, stearic acid, calciumhydroxide, talc, corn starch, sodium stearyl fumerate, alkali-metal andalkaline earth metal salts, such as aluminum, calcium, magnesium, zinc,stearic acid, sodium stearates, magnesium stearate, zinc stearate,waxes, Stearowet®, boric acid, sodium benzoate, sodium acetate, sodiumchloride, leucine, a polyethylene glycol or a methoxypolyethylene glycolsuch as Carbowax™, PEG 4000, PEG 5000, PEG 6000, propylene glycol,sodium oleate, glyceryl behenate, glyceryl palmitostearate, glycerylbenzoate, magnesium or sodium lauryl sulfate, and the like.

Suitable diluents for use in the solid dosage forms described hereininclude, but are not limited to, sugars (including lactose, sucrose, anddextrose), polysaccharides (including dextrates and maltodextrin),polyols (including mannitol, xylitol, and sorbitol), cyclodextrins andthe like.

Suitable wetting agents for use in the solid dosage forms describedherein include, for example, oleic acid, glyceryl monostearate, sorbitanmonooleate, sorbitan monolaurate, triethanolamine oleate,polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, quaternary ammonium compounds (e.g., Polyquat 10@), sodiumoleate, sodium lauryl sulfate, magnesium stearate, sodium docusate,triacetin, vitamin E TPGS and the like.

Suitable surfactants for use in the solid dosage forms described hereininclude, for example, sodium lauryl sulfate, sorbitan monooleate,polyoxyethylene sorbitan monooleate, polysorbates, polaxomers, bilesalts, glyceryl monostearate, copolymers of ethylene oxide and propyleneoxide, e.g., Pluronic® (BASF), and the like.

Suitable suspending agents for use in the solid dosage forms describedhere include, but are not limited to, polyvinylpyrrolidone, e.g.,polyvinylpyrrolidone K12, polyvinylpyrrolidone K17, polyvinylpyrrolidoneK25, or polyvinylpyrrolidone K30, polyethylene glycol, e.g., thepolyethylene glycol can have a molecular weight of about 300 to about6000, or about 3350 to about 4000, or about 7000 to about 5400, vinylpyrrolidone/vinyl acetate copolymer (S630), sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,polysorbate-80, hydroxyethylcellulose, sodium alginate, gums, such as,e.g., gum tragacanth and gum acacia, guar gum, xanthans, includingxanthan gum, sugars, cellulosics, such as, e.g., sodiumcarboxymethylcellulose, methylcellulose, sodium carboxymethylcellulose,hydroxypropylmethylcellulose, hydroxyethylcellulose, polysorbate-80,sodium alginate, polyethoxylated sorbitan monolaurate, polyethoxylatedsorbitan monolaurate, povidone and the like.

Suitable antioxidants for use in the solid dosage forms described hereininclude, for example, e.g., butylated hydroxytoluene (BHT), sodiumascorbate, and tocopherol.

It should be appreciated that there is considerable overlap betweenadditives used in the solid dosage forms described herein. Thus, theabove-listed additives should be taken as merely exemplary, and notlimiting, of the types of additives that can be included in solid dosageforms of the pharmaceutical compositions described herein. The amountsof such additives can be readily determined by one skilled in the art,according to the particular properties desired.

In various embodiments, the particles of a therapeutic agents and one ormore excipients are dry blended and compressed into a mass, such as atablet, having a hardness sufficient to provide a pharmaceuticalcomposition that substantially disintegrates within less than about 30minutes, less than about 35 minutes, less than about 40 minutes, lessthan about 45 minutes, less than about 50 minutes, less than about 55minutes, or less than about 60 minutes, after oral administration,thereby releasing the formulation into the gastrointestinal fluid.

In other embodiments, a powder including a therapeutic agent isformulated to include one or more pharmaceutical excipients and flavors.Such a powder is prepared, for example, by mixing the therapeutic agentand optional pharmaceutical excipients to form a bulk blend composition.Additional embodiments also include a suspending agent and/or a wettingagent. This bulk blend is uniformly subdivided into unit dosagepackaging or multi-dosage packaging units.

In still other embodiments, effervescent powders are also prepared.Effervescent salts have been used to disperse medicines in water fororal administration.

In some embodiments, the pharmaceutical dosage forms are formulated toprovide a controlled release of a therapeutic agent. Controlled releaserefers to the release of the therapeutic agent from a dosage form inwhich it is incorporated according to a desired profile over an extendedperiod of time. Controlled release profiles include, for example,sustained release, prolonged release, pulsatile release, and delayedrelease profiles. In contrast to immediate release compositions,controlled release compositions allow delivery of an agent to a subjectover an extended period of time according to a predetermined profile.Such release rates can provide therapeutically effective levels of agentfor an extended period of time and thereby provide a longer period ofpharmacologic response while minimizing side effects as compared toconventional rapid release dosage forms. Such longer periods of responseprovide for many inherent benefits that are not achieved with thecorresponding short acting, immediate release preparations.

In some embodiments, the solid dosage forms described herein areformulated as enteric coated delayed release oral dosage forms, i.e., asan oral dosage form of a pharmaceutical composition as described hereinwhich utilizes an enteric coating to affect release in the smallintestine or large intestine. In one aspect, the enteric coated dosageform is a compressed or molded or extruded tablet/mold (coated oruncoated) containing granules, powder, pellets, beads or particles ofthe active ingredient and/or other composition components, which arethemselves coated or uncoated. In one aspect, the enteric coated oraldosage form is in the form of a capsule containing pellets, beads orgranules, which include a therapeutic agent that are coated or uncoated.

Any coatings should be applied to a sufficient thickness such that theentire coating does not dissolve in the gastrointestinal fluids at pHbelow about 5, but does dissolve at pH about 5 and above. Coatings aretypically selected from any of the following: Shellac—this coatingdissolves in media of pH >7; Acrylic polymers—examples of suitableacrylic polymers include methacrylic acid copolymers and ammoniummethacrylate copolymers. The Eudragit series E, L, S, RL, RS and NE(Rohm Pharma) are available as solubilized in organic solvent, aqueousdispersion, or dry powders. The Eudragit series RL, NE, and RS areinsoluble in the gastrointestinal tract but are permeable and are usedprimarily for colonic targeting. The Eudragit series E dissolve in thestomach. The Eudragit series L, L-30D and S are insoluble in stomach anddissolve in the intestine; Poly Vinyl Acetate Phthalate (PVAP)—PVAPdissolves in pH >5, and it is much less permeable to water vapor andgastric fluids. Conventional coating techniques such as spray or pancoating are employed to apply coatings. The coating thickness must besufficient to ensure that the oral dosage form remains intact until thedesired site of topical delivery in the intestinal tract is reached.

In other embodiments, the formulations described herein are deliveredusing a pulsatile dosage form. A pulsatile dosage form is capable ofproviding one or more immediate release pulses at predetermined timepoints after a controlled lag time or at specific sites. Exemplarypulsatile dosage forms and methods of their manufacture are disclosed inU.S. Pat. Nos. 5,011,692, 5,017,381, 5,229,135, 5,840,329 and 5,837,284.In one embodiment, the pulsatile dosage form includes at least twogroups of particles, (i.e. multiparticulate) each containing theformulation described herein. The first group of particles provides asubstantially immediate dose of a therapeutic agent upon ingestion by amammal. The first group of particles can be either uncoated or include acoating and/or sealant. In one aspect, the second group of particlescomprises coated particles. The coating on the second group of particlesprovides a delay of from about 2 hours to about 7 hours followingingestion before release of the second dose. Suitable coatings forpharmaceutical compositions are described herein or known in the art.

In some embodiments, pharmaceutical formulations are provided thatinclude particles of a therapeutic agent and at least one dispersingagent or suspending agent for oral administration to a subject. Theformulations may be a powder and/or granules for suspension, and uponadmixture with water, a substantially uniform suspension is obtained.

In some embodiments, particles formulated for controlled release areincorporated in a gel or a patch or a wound dressing.

In one aspect, liquid formulation dosage forms for oral administrationand/or for topical administration as a wash are in the form of aqueoussuspensions selected from the group including, but not limited to,pharmaceutically acceptable aqueous oral dispersions, emulsions,solutions, elixirs, gels, and syrups. See, e.g., Singh et al.,Encyclopedia of Pharmaceutical Technology, 2nd Ed., pp. 754-757 (2002).In addition to the particles of a therapeutic agent, the liquid dosageforms include additives, such as: (a) disintegrating agents; (b)dispersing agents; (c) wetting agents; (d) at least one preservative,(e) viscosity enhancing agents, (f) at least one sweetening agent, and(g) at least one flavoring agent. In some embodiments, the aqueousdispersions can further include a crystalline inhibitor.

In some embodiments, the liquid formulations also include inert diluentscommonly used in the art, such as water or other solvents, solubilizingagents, and emulsifiers. Exemplary emulsifiers are ethyl alcohol,isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,benzyl benzoate, propyleneglycol, 1,3-butyleneglycol, dimethylformamide,sodium lauryl sulfate, sodium docusate, cholesterol, cholesterol esters,taurocholic acid, phosphatidylcholine, oils, such as cottonseed oil,groundnut oil, corn germ oil, olive oil, castor oil, and sesame oil,glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols, fatty acidesters of sorbitan, or mixtures of these substances, and the like.

Furthermore, pharmaceutical compositions optionally include one or morepH adjusting agents or buffering agents, including acids such as acetic,boric, citric, lactic, phosphoric and hydrochloric acids; bases such assodium hydroxide, sodium phosphate, sodium borate, sodium citrate,sodium acetate, sodium lactate and tris-hydroxymethylaminomethane; andbuffers such as citrate/dextrose, sodium bicarbonate and ammoniumchloride. Such acids, bases and buffers are included in an amountrequired to maintain pH of the composition in an acceptable range.

Additionally, pharmaceutical compositions optionally include one or moresalts in an amount required to bring osmolality of the composition intoan acceptable range. Such salts include those having sodium, potassiumor ammonium cations and chloride, citrate, ascorbate, borate, phosphate,bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable saltsinclude sodium chloride, potassium chloride, sodium thiosulfate, sodiumbisulfite and ammonium sulfate.

Other pharmaceutical compositions optionally include one or morepreservatives to inhibit microbial activity. Suitable preservativesinclude mercury-containing substances such as merfen and thiomersal;stabilized chlorine dioxide; and quaternary ammonium compounds such asbenzalkonium chloride, cetyltrimethylammonium bromide andcetylpyridinium chloride.

In one embodiment, the aqueous suspensions and dispersions describedherein remain in a homogenous state, as defined in The USP Pharmacists'Pharmacopeia (2005 edition, chapter 905), for at least 4 hours. In oneembodiment, an aqueous suspension is re-suspended into a homogenoussuspension by physical agitation lasting less than 1 minute. In stillanother embodiment, no agitation is necessary to maintain a homogeneousaqueous dispersion.

Examples of disintegrating agents for use in the aqueous suspensions anddispersions include, but are not limited to, a starch, e.g., a naturalstarch such as corn starch or potato starch, a pregelatinized starch, orsodium starch glycolate; a cellulose such as methylcrystallinecellulose, methylcellulose, croscarmellose, or a cross-linked cellulose,such as cross-linked sodium carboxymethylcellulose, cross-linkedcarboxymethylcellulose, or cross-linked croscarmellose; a cross-linkedstarch such as sodium starch glycolate; a cross-linked polymer such ascrospovidone; a cross-linked polyvinylpyrrolidone; alginate such asalginic acid or a salt of alginic acid such as sodium alginate; a gumsuch as agar, guar, locust bean, Karaya, pectin, or tragacanth; sodiumstarch glycolate; bentonite; a natural sponge; a surfactant; a resinsuch as a cation-exchange resin; citrus pulp; sodium lauryl sulfate;sodium lauryl sulfate in combination starch; and the like.

In some embodiments, the dispersing agents suitable for the aqueoussuspensions and dispersions described herein include, for example,hydrophilic polymers, electrolytes, Tween® 60 or 80, PEG,polyvinylpyrrolidone, and the carbohydrate-based dispersing agents suchas, for example, hydroxypropylcellulose and hydroxypropyl celluloseethers, hydroxypropyl methylcellulose and hydroxypropyl methylcelluloseethers, carboxymethylcellulose sodium, methylcellulose,hydroxyethylcellulose, hydroxypropylmethyl-cellulose phthalate,hydroxypropylmethyl-cellulose acetate stearate, noncrystallinecellulose, magnesium aluminum silicate, triethanolamine, polyvinylalcohol (PVA), polyvinylpyrrolidone/vinyl acetate copolymer,4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide andformaldehyde (also known as tyloxapol), poloxamers; and poloxamines. Inother embodiments, the dispersing agent is selected from a group notcomprising one of the following agents: hydrophilic polymers;electrolytes; Tween® 60 or 80; PEG; polyvinylpyrrolidone (PVP);hydroxypropylcellulose and hydroxypropyl cellulose ethers; hydroxypropylmethylcellulose and hydroxypropyl methylcellulose ethers;carboxymethylcellulose sodium; methylcellulose; hydroxyethylcellulose;hydroxypropylmethyl-cellulose phthalate; hydroxypropylmethyl-celluloseacetate stearate; noncrystalline cellulose; magnesium aluminum silicate;triethanolamine; polyvinyl alcohol (PVA);4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene oxide andformaldehyde; poloxamers; or poloxamines.

Wetting agents suitable for the aqueous suspensions and dispersionsdescribed herein include, but are not limited to, cetyl alcohol,glycerol monostearate, polyoxyethylene sorbitan fatty acid esters (e.g.,the commercially available Tweens® such as e.g., Tween 20@ and Tween80@, and polyethylene glycols, oleic acid, glyceryl monostearate,sorbitan monooleate, sorbitan monolaurate, triethanolamine oleate,polyoxyethylene sorbitan monooleate, polyoxyethylene sorbitanmonolaurate, sodium oleate, sodium lauryl sulfate, sodium docusate,triacetin, vitamin E TPGS, sodium taurocholate, simethicone,phosphatidylcholine and the like.

Suitable preservatives for the aqueous suspensions or dispersionsdescribed herein include, for example, potassium sorbate, parabens(e.g., methylparaben and propylparaben), benzoic acid and its salts,other esters of parahydroxybenzoic acid such as butylparaben, alcoholssuch as ethyl alcohol or benzyl alcohol, phenolic compounds such asphenol, or quaternary compounds such as benzalkonium chloride.Preservatives, as used herein, are incorporated into the dosage form ata concentration sufficient to inhibit microbial growth.

Suitable viscosity enhancing agents for the aqueous suspensions ordispersions described herein include, but are not limited to, methylcellulose, xanthan gum, carboxymethyl cellulose, hydroxypropylcellulose, hydroxypropylmethyl cellulose, Plasdon® S-630, carbomer,polyvinyl alcohol, alginates, acacia, chitosans and combinationsthereof. The concentration of the viscosity enhancing agent will dependupon the agent selected and the viscosity desired.

Examples of sweetening agents suitable for the aqueous suspensions ordispersions described herein include, for example, acacia syrup,acesulfame K, alitame, aspartame, chocolate, cinnamon, citrus, cocoa,cyclamate, dextrose, fructose, ginger, glycyrrhetinate, glycyrrhiza(licorice) syrup, monoammonium glyrrhizinate (MagnaSweet®), malitol,mannitol, menthol, neohesperidine DC, neotame, Prosweet® Powder,saccharin, sorbitol, stevia, sucralose, sucrose, sodium saccharin,saccharin, aspartame, acesulfame potassium, mannitol, sucralose,tagatose, thaumatin, vanilla, xylitol, or any combination thereof.

In some embodiments, a therapeutic agent is prepared as transdermaldosage form. In some embodiments, the transdermal formulations describedherein include at least three components: (1) a therapeutic agent; (2) apenetration enhancer; and (3) an optional aqueous adjuvant. In someembodiments the transdermal formulations include additional componentssuch as, but not limited to, gelling agents, creams and ointment bases,and the like. In some embodiments, the transdermal formulation ispresented as a patch or a wound dressing. In some embodiments, thetransdermal formulation further include a woven or non-woven backingmaterial to enhance absorption and prevent the removal of thetransdermal formulation from the skin. In other embodiments, thetransdermal formulations described herein can maintain a saturated orsupersaturated state to promote diffusion into the skin.

In one aspect, formulations suitable for transdermal administration of atherapeutic agent described herein employ transdermal delivery devicesand transdermal delivery patches and can be lipophilic emulsions orbuffered, aqueous solutions, dissolved and/or dispersed in a polymer oran adhesive. In one aspect, such patches are constructed for continuous,pulsatile, or on demand delivery of pharmaceutical agents. Stillfurther, transdermal delivery of the therapeutic agents described hereincan be accomplished by means of iontophoretic patches and the like. Inone aspect, transdermal patches provide controlled delivery of atherapeutic agent. In one aspect, transdermal devices are in the form ofa bandage comprising a backing member, a reservoir containing thetherapeutic agent optionally with carriers, optionally a ratecontrolling barrier to deliver the therapeutic agent to the skin of thehost at a controlled and predetermined rate over a prolonged period oftime, and means to secure the device to the skin.

In further embodiments, topical formulations include gel formulations(e.g., gel patches which adhere to the skin). In some of suchembodiments, a gel composition includes any polymer that forms a gelupon contact with the body (e.g., gel formulations comprising hyaluronicacid, pluronic polymers, poly(lactic-co-glycolic acid (PLGA)-basedpolymers or the like). In some forms of the compositions, theformulation comprises a low-melting wax such as, but not limited to, amixture of fatty acid glycerides, optionally in combination with cocoabutter which is first melted. Optionally, the formulations furthercomprise a moisturizing agent.

In certain embodiments, delivery systems for pharmaceutical therapeuticagents may be employed, such as, for example, liposomes and emulsions.In certain embodiments, compositions provided herein can also include anmucoadhesive polymer, selected from among, for example,carboxymethylcellulose, carbomer (acrylic acid polymer),poly(methylmethacrylate), polyacrylamide, polycarbophil, acrylicacid/butyl acrylate copolymer, sodium alginate and dextran.

In some embodiments, a therapeutic agent described herein may beadministered topically and can be formulated into a variety of topicallyadministrable compositions, such as solutions, suspensions, lotions,gels, pastes, medicated sticks, balms, creams or ointments. Suchpharmaceutical therapeutic agents can contain solubilizers, stabilizers,tonicity enhancing agents, buffers and preservatives.

Methods of Monitoring Treatment

In certain embodiments, described herein are methods for evaluating aneffect of a treatment described herein. In some instances, the treatmentcomprises administration with an inhibitor of TL1A activity orexpression and optionally, one or more additional therapeutic agents. Insome instances, the treatment is monitored by evaluating the quantity ofTL1A in the subject prior to and/or after administration of atherapeutic agent.

I. Numbered Embodiments

Non-limiting embodiments of the present disclosure include thefollowing:

-   1. A method of inhibiting or reducing TL1A activity or expression in    a subject having or suspected of having at least one of an    inflammatory, fibrostenotic, and fibrotic, disease or condition the    method comprising:    -   a) identifying the subject as being a carrier of a genotype        comprising a polymorphism provided in Table 1 or Table 4, or a        polymorphism in linkage disequilibrium (LD) therewith; and    -   b) administering to the subject a therapeutically effective        amount of an anti-TL1A antibody, thereby inhibiting or reducing        TL1A activity or expression in the subject.-   2. The method of embodiment 1, provided that the inflammatory    disease comprises Crohn's disease.-   3. The method of embodiment 2, provided that the Crohn's disease    comprises ileal, ileocolonic, or colonic Crohn's disease.-   4. The method of embodiment 1, provided that the inflammatory    disease comprises ulcerative colitis (UC).-   5. The method of embodiment 4, provided that the UC is medically    refractory UC.-   6. The method of any of embodiments 1-5, wherein identifying the    subject as being a carrier of the genotype of step (a) comprises:    -   a) contacting a sample comprising genetic material from the        subject with a nucleic acid sequence capable of hybridizing to        at least 10 contiguous nucleobases comprising a risk allele        located at nucleoposition 501 within any one of SEQ ID NOS:        1-48, or 57-59; and    -   b) detecting binding between the nucleic acid sequence and the        at least 10 contiguous nucleobases comprising the risk allele.-   7. The method of embodiment 6, provided that the standard    hybridization conditions comprise an annealing temperature between    about 35° C. and about 65° C.-   8. The method of embodiment 6 or embodiment 7, provided that the    standard hybridization conditions are performed with a TaqMan master    mix solution.-   9. The method of any of embodiments 6-8, provided that the nucleic    acid sequence is conjugated to a detectable molecule.-   10. The method of embodiment 9, provided that the detectable    molecule comprises a fluorophore.-   11. The method of any of embodiments 6-10, provided that the nucleic    acid sequence is conjugated to a quencher.-   12. The method of any of embodiments 6-11, provided that the sample    comprising genetic material from the subject is amplified genetic    material obtained from a nucleic acid amplification assay.-   13. The method of embodiment 12, provided that the nucleic acid    amplification assay comprises amplification of DNA from the subject    with a pair of primers capable of amplifying at least 15 contiguous    nucleobases comprising the risk allele located at nucleoposition 501    within any one of SEQ ID NOS: 1-48, or 57-59, the pair of primers    comprising a first primer and a second primer.-   14. The method of embodiment 12, provided that the first primer    comprises a nucleic acid sequence complimentary to at least 15    contiguous nucleobases upstream of the risk allele located at    nucleobase 501 within any one of SEQ ID NOS: 1-48, or 57-59, and the    second primer comprises a nucleic acid sequence complimentary to at    least 15 contiguous nucleobases downstream of the risk allele    located at nucleobase 501 within any one of SEQ ID NOS: 1-48, or    57-59.-   15. The method of any of embodiments 1-14, provided that the subject    has been determined to be a carrier of the genotype by a process    comprising DNA sequencing.-   16. The method of any of embodiments 1-15, provided that the subject    further comprises soluble TL1A at a level greater than a control    level derived from a non-diseased individual or population of    non-diseased individuals.-   17. The method of any of embodiments 1-16, provided that the subject    is homozygous for the genotype.-   18. The method of any of embodiments 1-17, wherein the genotype    comprises at least two polymorphisms provided in Table 1 or Table 4.-   19. The method of any of embodiments 1-17, wherein the genotype    comprises at least three polymorphisms provided in Table 1 or Table    4.-   20. The method of any of embodiments 1-19, wherein the genotype    comprises a polymorphism selected from the group consisting of a “G”    allele at rs11897732 (SEQ ID NO: 1), an “A” allele at rs6740739 (SEQ    ID NO: 2), a “G” allele at rs17796285 (SEQ ID NO: 3), an “A” allele    at rs7935393 (SEQ ID NO: 4), a “G” allele at rs12934476 (SEQ ID NO:    5), an “A” allele at rs12457255 (SEQ ID NO: 6), an “A” allele at    rs2070557 (SEQ ID NO: 7), an “A” allele at rs4246905 (SEQ ID NO: 8),    an “A” allele at rs10974900 (SEQ ID NO: 9), a “C” allele at    rs12434976 (SEQ ID NO: 10), an “A” allele at rrs16901748 (SEQ ID NO:    11), an “A” allele at rs2815844 (SEQ ID NO: 12), a “G” allele at    rs889702 (SEQ ID NO: 13), a “C” allele at rs2409750 (SEQ ID NO: 14),    an “A” allele at rs1541020 (SEQ ID NO: 15), a “T” allele at    rs4942248 (SEQ ID NO: 16), a “G” allele at rs12934476 (SEQ ID NO:    17), an “A” allele at rs12457255 (SEQ ID NO: 18), an “A” allele at    rs2297437 (SEQ ID NO: 19), a “G” allele at rs41309367 (SEQ ID NO:    20), an “A” allele at rs10733509 (SEQ ID NO: 21), a “G” allele at    rs10750376 (SEQ ID NO: 22), a “G” allele at rs10932456 (SEQ ID NO:    23), an “A” allele at rs1326860 (SEQ ID NO: 24), a “G” allele at    rs1528663 (SEQ ID NO: 25), a “C” allele at rs1892231 (SEQ ID NO:    26), an “A” allele at rs951279 (SEQ ID NO: 27), an “A” allele at    rs9806914 (SEQ ID NO: 28), an “A” allele at rs7935393 (SEQ ID NO:    29), a “G” allele at rs1690492 (SEQ ID NO: 30), an “A” allele at    rs420726 (SEQ ID NO: 31), a “T” allele at rs7759385 (SEQ ID NO: 32),    an “A” allele at rs10974900 (SEQ ID NO: 33), an “A” allele at    rs1326860 (SEQ ID NO: 34), a “C” allele at rs2548147 (SEQ ID NO:    35), an “A” allele at rs2815844 (SEQ ID NO: 36), a “G” allele at    rs889702 (SEQ ID NO: 37), an “A” allele at rs9806914 (SEQ ID NO:    38), an “A” allele at rs6478109 (SEQ ID NO: 39), a “C” allele at    rs7278257 (SEQ ID NO: 40), an “A” allele at rs11221332 (SEQ ID NO:    41), an “A” allele at rs56124762 (SEQ ID NO: 57), a “G” at rs2070558    (SEQ ID NO: 58), and a “T” allele at rs2070561 (SEQ ID NO: 59).-   21. The method of embodiments 1-20, wherein the inhibitor of TL1A    activity or expression is an anti-TL1A antibody.-   22. The method of embodiment 21, wherein the anti-TL1A antibody is    selected from Table 2B.-   23. The method of embodiment 21, wherein the anti-TL1A antibody    comprises an amino acid sequence provided in Table 2A.-   24. The method of embodiment 21, wherein the anti-TL1A antibody    binds to the same region of human TL1A as a reference antibody    selected from Table 2B.-   25. The method of embodiment 21, wherein the anti-TL1A antibody    binds to the same region of human TL1A as a reference antibody, the    reference antibody comprising an amino acid sequence provided in    Table 2A.-   26. The method of embodiments 22-25, wherein the anti-TL1A antibody    is a neutralizing TL1A antibody.-   27. The method of embodiments 22-26, wherein the anti-TL1A antibody    is an antagonist of TL1A.-   28. A method of treating an inflammatory, fibrostenotic, and    fibrotic, disease or condition in a subject comprising administering    to the subject a therapeutically effective amount of an inhibitor of    TL1A activity or expression, provided a presence of a genotype is    detected in a sample obtained from the subject.-   29. A method of treating an inflammatory, fibrostenotic, and    fibrotic, disease or condition in a subject comprising:    -   a) analyzing a sample obtained from a subject to detect a        presence or an absence of a genotype;    -   b) detect the presence of the genotype in the sample obtained        from the subject;    -   c) administering to the subject a therapeutically effective        amount of an inhibitor of TL1A activity or expression.-   30. The method of embodiment 28-29, provided that the inflammatory    disease comprises Crohn's disease.-   31. The method of embodiment 30, provided that the Crohn's disease    comprises ileal, ileocolonic, or colonic Crohn's disease.-   32. The method of embodiment 28-29, provided that the inflammatory    disease is ulcerative colitis (UC).-   33. The method of embodiment 32, provided that the UC is medically    refractory UC.-   34. The method of any of embodiments 29-33, wherein the presence of    the genotype is detected in the sample obtained from the subject by:    -   a) contacting the sample comprising genetic material from the        subject with a nucleic acid sequence capable of hybridizing to        at least 10 contiguous nucleobases comprising a risk allele        located at nucleoposition 501 within any one of SEQ ID NOS:        1-48, or 57-59; and    -   b) detecting binding between the nucleic acid sequence and the        at least 10 contiguous nucleobases comprising the risk allele.-   35. The method of embodiment 34, provided that the standard    hybridization conditions comprise an annealing temperature between    about 35° C. and about 65° C.-   36. The method of embodiment 34 or embodiment 35, provided that the    standard hybridization conditions are performed with a TaqMan master    mix solution.-   37. The method of any of embodiments 34-36, provided that the    nucleic acid sequence is conjugated to a detectable molecule.-   38. The method of embodiment 37, provided that the detectable    molecule comprises a fluorophore.-   39. The method of any of embodiments 34-38, provided that the    nucleic acid sequence is conjugated to a quencher.-   40. The method of any of embodiments 34-39, provided that the sample    comprising genetic material from the subject is amplified genetic    material obtained from a nucleic acid amplification assay.-   41. The method of embodiment 40, provided that the nucleic acid    amplification assay comprises amplification of DNA from the subject    with a pair of primers capable of amplifying at least 15 contiguous    nucleobases comprising the risk allele located at nucleoposition 501    within any one of SEQ ID NOS: 1-48, or 57-59, the pair of primers    comprising a first primer and a second primer.-   42. The method of embodiment 41, provided that the first primer    comprises a nucleic acid sequence complimentary to at least 15    contiguous nucleobases upstream of the risk allele located at    nucleobase 501 within any one of SEQ ID NOS: 1-48, or 57-59, and the    second primer comprises a nucleic acid sequence complimentary to at    least 15 contiguous nucleobases downstream of the risk allele    located at nucleobase 501 within any one of SEQ ID NOS: 1-48, or    57-59.-   43. The method of any of embodiments 29-42 the presence of the    genotype is detected in the sample obtained from the subject by a    process comprising DNA sequencing.-   44. The method of any of embodiments 29-43, provided that the    subject further comprises soluble TL1A at a level greater than a    control level derived from a non-diseased individual or population    of non-diseased individuals.-   45. The method of any of embodiments 29-44, provided that the    subject is homozygous for the genotype.-   46. The method of any of embodiments 29-45, wherein the genotype    comprises at least two polymorphisms provided in Table 1 or Table 4.-   47. The method of any of embodiments 29-46, wherein the genotype    comprises at least three polymorphisms provided in Table 1 or Table    4.-   48. The method of any of embodiments 29-47, wherein the genotype    comprises a polymorphism selected from the group consisting of a “G”    allele at rs11897732 (SEQ ID NO: 1), an “A” allele at rs6740739 (SEQ    ID NO: 2), a “G” allele at rs17796285 (SEQ ID NO: 3), an “A” allele    at rs7935393 (SEQ ID NO: 4), a “G” allele at rs12934476 (SEQ ID NO:    5), an “A” allele at rs12457255 (SEQ ID NO: 6), an “A” allele at    rs2070557 (SEQ ID NO: 7), an “A” allele at rs4246905 (SEQ ID NO: 8),    an “A” allele at rs10974900 (SEQ ID NO: 9), a “C” allele at    rs12434976 (SEQ ID NO: 10), an “A” allele at rrs16901748 (SEQ ID NO:    11), an “A” allele at rs2815844 (SEQ ID NO: 12), a “G” allele at    rs889702 (SEQ ID NO: 13), a “C” allele at rs2409750 (SEQ ID NO: 14),    an “A” allele at rs1541020 (SEQ ID NO: 15), a “T” allele at    rs4942248 (SEQ ID NO: 16), a “G” allele at rs12934476 (SEQ ID NO:    17), an “A” allele at rs12457255 (SEQ ID NO: 18), an “A” allele at    rs2297437 (SEQ ID NO: 19), a “G” allele at rs41309367 (SEQ ID NO:    20), an “A” allele at rs10733509 (SEQ ID NO: 21), a “G” allele at    rs10750376 (SEQ ID NO: 22), a “G” allele at rs10932456 (SEQ ID NO:    23), an “A” allele at rs1326860 (SEQ ID NO: 24), a “G” allele at    rs1528663 (SEQ ID NO: 25), a “C” allele at rs1892231 (SEQ ID NO:    26), an “A” allele at rs951279 (SEQ ID NO: 27), an “A” allele at    rs9806914 (SEQ ID NO: 28), an “A” allele at rs7935393 (SEQ ID NO:    29), a “G” allele at rs1690492 (SEQ ID NO: 30), an “A” allele at    rs420726 (SEQ ID NO: 31), a “T” allele at rs7759385 (SEQ ID NO: 32),    an “A” allele at rs10974900 (SEQ ID NO: 33), an “A” allele at    rs1326860 (SEQ ID NO: 34), a “C” allele at rs2548147 (SEQ ID NO:    35), an “A” allele at rs2815844 (SEQ ID NO: 36), a “G” allele at    rs889702 (SEQ ID NO: 37), an “A” allele at rs9806914 (SEQ ID NO:    38), an “A” allele at rs6478109 (SEQ ID NO: 39), a “C” allele at    rs7278257 (SEQ ID NO: 40), an “A” allele at rs11221332 (SEQ ID    NO: 41) an “A” allele at rs56124762 (SEQ ID NO: 57), a “G” at    rs2070558 (SEQ ID NO: 58), and a “T” allele at rs2070561 (SEQ ID NO:    59).-   49. The method of embodiments 29-48, wherein the inhibitor of TL1A    activity or expression is an anti-TL1A antibody.-   50. The method of embodiment 49, wherein the anti-TL1A antibody is    selected from Table 2B.-   51. The method of embodiment 49, wherein the anti-TL1A antibody    comprises an amino acid sequence provided in Table 2A.-   52. The method of embodiment 49, wherein the anti-TL1A antibody    binds to the same region of human TL1A as a reference antibody    selected from Table 2B.-   53. The method of embodiment 49, wherein the anti-TL1A antibody    binds to the same region of human TL1A as a reference antibody, the    reference antibody comprising an amino acid sequence provided in    Table 2A.-   54. The method of embodiments 49-53, wherein the anti-TL1A antibody    is a neutralizing TL1A antibody.-   55. The method of embodiments 49-54, wherein the anti-TL1A antibody    is an antagonist of TL1A.-   56. A method of characterizing at least one of an inflammatory,    fibrostenotic, and fibrotic, disease or condition of a subject, the    method comprising assaying genetic material from the subject to    identify the presence or absence of a genotype comprising a    polymorphism provided in Table 1 or Table 4.-   57. The method of embodiment 56, further comprising assigning a more    favorable prognosis to treatment with an inhibitor of TL1A activity    or expression when the genotype is present.-   58. The method of embodiment 56, further comprising assigning a less    favorable prognosis to with an inhibitor of TL1A activity or    expression when the genotype is absent.-   59. The method of embodiment 56, further comprising assigning the    subject to treatment with an inhibitor of TL1A activity or    expression when the genotype is present.-   60. The method of embodiment 56, further comprising prescribing to    the subject an inhibitor of TL1A activity or expression when the    genotype is present.-   61. The method of embodiment 56, further comprising administering to    the subject an inhibitor of anti-CD30 ligand activity or expression    when the genotype is present.-   62. The method of any of embodiments 57-61, provided that the    inhibitor of TL1A activity or expression is an anti-TL1A antibody or    antigen-binding fragment thereof.-   63. The method of any of embodiments 56-62, provided that assaying    comprises amplifying from the genetic material comprising at least    15 contiguous nucleobases including a risk allele located at    nucleoposition 501 within any one of SEQ ID NOS: 1-48, or 57-59    using a pair of primers comprising a first primer and a second    primer.-   64. The method of any of embodiment 63, provided that the first    primer comprises a nucleic acid sequence complimentary to at least    15 contiguous nucleobases upstream of the risk allele located at    nucleobase 501 within any one of SEQ ID NOS: 1-48, or 57-59, and the    second primer comprises a nucleic acid sequence complimentary to at    least 15 contiguous nucleobases downstream of the risk allele    located at nucleobase 501 within any one of SEQ ID NOS: 1-48, or    57-59.-   65. The method of any of embodiments 65-73, provided that assaying    comprises hybridizing to the genetic material a nucleic acid    comprising any one of SEQ ID NOS: 1-48, or 57-59.-   66. The method of embodiment 65, provided that the nucleic acid    sequence is conjugated to a detectable molecule.-   67. The method of embodiment 66, provided that the detectable    molecule comprises a fluorophore.-   68. The method of any of embodiments 65-67, provided that the    nucleic acid sequence is conjugated to a quencher.-   69. The method of any of embodiments 56-62, provided that assaying    comprises DNA sequencing.-   70. The method of any of embodiments 56-69, further comprising    measuring the level of TL1A in the subject.-   71. The method of any of embodiments 56-70, provided that the    subject is homozygous for the genotype.-   72. The method of embodiments 56-71, wherein the genotype comprises    at least two polymorphisms provided in Table 1 or Table 4.-   73. The method of any of embodiments 56-72, wherein the genotype    comprises at least three polymorphisms provided in Table 1 or Table    4-   74. The method of any one of embodiments 56-73, wherein the genotype    comprises at least one polymorphism comprising a non-reference    allele.-   75. The method of any of embodiments 56-74, further comprising    characterizing the at least one of the inflammatory, the    fibrostenotic, and the fibrotic, disease or condition as Crohn's    disease (CD) provided the genotype is present.-   76. The method of embodiment 75, provided that the CD comprises    ileal, ileocolonic, or colonic CD.-   77. The method of any of embodiments 56-76, further comprising    characterizing the at least one of the inflammatory, the    fibrostenotic, and the fibrotic, disease or condition as a    ulcerative colitis (UC), provided the genotype is present.-   78. The method of embodiment 77, provided that the fibrotic disease    is medically refractory UC.-   79. The method of embodiment 62, wherein the anti-TL1A antibody is    selected from Table 2B.-   80. The method of embodiment 62, wherein the anti-TL1A antibody    comprises an amino acid sequence provided in Table 2A.-   81. The method of embodiment 62, wherein the anti-TL1A antibody    binds to the same region of human TL1A as a reference antibody    selected from Table 2B.-   82. The method of embodiment 62, wherein the anti-TL1A antibody    binds to the same region of human TL1A as a reference antibody, the    reference antibody comprising an amino acid sequence provided in    Table 2A.-   83. The method of embodiments 79-82, wherein the anti-TL1A antibody    is a neutralizing TL1A antibody.-   84. The method of embodiments 79-83, wherein the anti-TL1A antibody    is an antagonist of TL1A.-   85. A method for detecting a genotype of interest in a subject    comprising at least one of an inflammatory, a fibrostenotic, and a    fibrotic, disease or condition, the method comprising:    -   (a) contacting genetic material from the subject with a        composition sufficiently complementary to and capable of        hybridizing to the genotype of interest, the composition        comprising:        -   (i) a detectably labeled oligonucleotide probe comprising at            least 10 contiguous nucleobases provided in any one of SEQ            ID NOS: 1-48, or 57-59,        -   (ii) a detectably labeled oligonucleotide probe comprising            at least 10 contiguous nucleobases provided in any one of            SEQ ID NOS: 1-48, or 57-59,        -   (iii) a detectably labeled oligonucleotide probe comprising            at least 10 contiguous nucleobases provided in any one of            SEQ ID NOS: 1-48, or 57-59,        -   (iv) a detectably labeled oligonucleotide probe comprising a            nucleic acid sequence that differs from a probe selected            from the group consisting of (i)-(iii) by up to three            nucleobases, provided the detectably labeled oligonucleotide            probe of (iv) hybridizes to the genotype of interest,        -   (v) a detectably labeled oligonucleotide probe comprising a            nucleic acid sequence complementary to a probe selected from            the group consisting of (i)-(iv), or        -   (vi) a combination of probes selected from the group            consisting of (i)-(v), wherein the detectably labeled            oligonucleotide probe of (i), (ii), and (iii) are different,    -   (b) detecting the presence or absence of hybridization of the        genetic material with the composition using the detectably        labeled probe, whereby hybridization of the genetic material        with the composition is indicative of the presence of the        genotype of interest in the subject.-   86. The method of embodiment 85, provided that the presence of the    genotype of interest is indicative of the subject comprising    elevated levels of TL1A.-   87. The method of embodiment 85 or embodiment 86, provided that the    inflammatory disease comprises Crohn's disease (CD).-   88. The method of embodiment 87, provided that the CD comprises    ileal, ileocolonic, or colonic CD.-   89. The method of any of embodiments 89-92, provided that the    inflammatory disease is ulcerative colitis (UC).-   90. A method of treating the at least one of an inflammatory    disease, a fibrostenotic disease, in the subject of any one of    embodiments 85-89, the method comprising:    -   a) administering to the subject of any of embodiments 85-93 a        therapeutically effective amount of an inhibitor of TL1A        activity or expression, provided that the subject comprises the        genotype of interest.-   91. The method of embodiment 90, provided that the inhibitor of TL1A    activity comprises an anti-TL1A ligand antibody or antigen binding    fragment thereof.-   92. A composition comprising at least 10 but less than 50 contiguous    nucleobase residues of any one of SEQ ID NOS: 1-48, or 57-59 or its    complement, wherein the contiguous nucleobase residues comprise the    nucleobase at position 501 of the any one of SEQ ID NOS: 1-48, or    57-59, and wherein the contiguous nucleobase residues are connected    to a detectable molecule.-   93. The composition of embodiment 92, provided that the detectable    molecule is a fluorophore.-   94. The composition of embodiments 92-93, wherein the contiguous    nucleobase residues comprise the nucleobase at position 501 of any    one of SEQ ID NOS: 1-48, or 57-59.-   95. The composition of embodiments 92-93, wherein the contiguous    nucleobase residues comprise the nucleobase at position 501 of any    one of SEQ ID NOS: 60-108, or 364141-364142.-   96. The composition of embodiments 92-95, provided that the    contiguous nucleobase residues are connected to a quencher.-   97. A kit comprising the composition of any of embodiments 92-96,    and a primer pair capable of amplifying at least 15 contiguous    nucleic acid molecules of any one of SEQ ID NOS: 1-48, or 57-59, the    at least 15 contiguous nucleic acid molecules comprising the nucleic    acid located at position 501 of any one of SEQ ID NOS: 1-48, or    57-59.-   98. A method comprising contacting DNA from a subject with the    composition of any of embodiments 92-96 or the kit of any of    embodiment 97 under conditions configured to hybridize the    composition to the DNA if the DNA comprises a sequence complementary    to the composition.-   99. A method comprising treating the subject of embodiment 98 with    an inhibitor of TL1A activity or expression, provided that the DNA    from the subject comprises the sequence complementary to the    composition.-   100. The method of embodiment 99, provided that the inhibitor of    TL1A comprises an anti-TL1A antibody or antigen binding fragment    thereof.-   101. A method of identifying a risk of developing a TL1A mediated    disease or condition comprising at least one of an inflammatory, a    fibrostenotic, and a fibrotic, disease or condition in a subject,    the method comprising:    -   a) assaying a sample obtained from the subject to identify the        presence of a genotype comprising a polymorphism provided in        Table 1 or Table 4, or a polymorphism in linkage disequilibrium        (LD) therewith; and    -   b) identifying the risk of developing at least one of an        inflammatory, a fibrostenotic, and a fibrotic, disease or        condition in the subject, provided the presence of the genotype        is identified in step (a).-   102. A method of selecting a subject for treatment, the method    comprising:    -   a) assaying a sample obtained from the subject to identify the        presence of a genotype comprising a polymorphism provided in        Table 1 or Table 4, or a polymorphism in linkage disequilibrium        (LD) therewith; and    -   b) selecting the subject for treatment with an inhibitor of TL1A        activity or expression, provided the presence of the genotype is        identified in step (a).-   103. The method of any of embodiments 101-102, provided that the    subject is homozygous for the genotype.-   104. The method of any of embodiments 101-103, wherein the genotype    comprises at least two polymorphisms provided in Table 1 or Table 4.-   105. The method of any of embodiments 101-104, wherein the genotype    comprises at least three polymorphisms provided in Table 1 or Table    4.-   106. The method of any of embodiments 101-105, wherein the genotype    comprises at least one polymorphism comprising a non-reference    allele.-   107. The method of embodiments 101-106, further comprising treating    the subject by administering to the subject a therapeutically    effective amount of an inhibitor of TL1A activity or expression.-   108. The method of embodiment 107, wherein the inhibitor of TL1A    activity or expression is an anti-TL1A antibody.-   109. The method of embodiment 108, wherein the anti-TL1A antibody is    selected from Table 2B.-   110. The method of embodiment 108, wherein the anti-TL1A antibody    comprises an amino acid sequence provided in Table 2A.-   111. The method of embodiment 108, wherein the anti-TL1A antibody    binds to the same region of human TL1A as a reference antibody    selected from Table 2B.-   112. The method of embodiment 108, wherein the anti-TL1A antibody    binds to the same region of human TL1A as a reference antibody, the    reference antibody comprising an amino acid sequence provided in    Table 2A.-   113. The method of embodiments 108-112, wherein the anti-TL1A    antibody is a neutralizing TL1A antibody.-   114. The method of embodiments 108-113, wherein the anti-TL1A    antibody is an antagonist of TL1A.-   115. The methods of embodiments 28-55 or 101-106, further comprising    administering a therapeutically effective amount of an additional    therapeutic agent.-   116. The method of embodiment 115, wherein the additional    therapeutic agent is a modulator of Receptor Interacting    Serine/Threonine Kinase 2 (RIPK2).-   117. The method of embodiment 115, wherein the additional    therapeutic agent is a modulator of G Protein-Coupled Receptor 35    (GPR35).-   118. The method of embodiment 115, wherein the additional    therapeutic agent is a modulator of CD30 ligand (CD30L) 119. The    method of embodiment 16, wherein the modulator of RIPK2 is selected    from the group consisting of Formula I-X.-   120. The method of embodiment 117, wherein the modulator of GPR35 is    selected from the group consisting of Formula I-XXVI.-   121. The method of embodiment 118, wherein the modulator of CD30L    comprises an amino acid sequence provided in Table 3.-   122. The method of any one of embodiments 1-121, further comprising    predicting a positive therapeutic response in a subject to a    treatment with the inhibitor of TL1A activity or expression with a    positive predictive value of at least or about 50%, 55%, 60%, 65%,    70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% 95%, 96%, 97%, 98%, 99%,    or 100%.-   123. The method of any one of embodiments 1-122, further comprising    predicting a positive therapeutic response in a subject to a    treatment with the inhibitor of TL1A activity or expression with a    specificity of at least or about 50%, 55%, 60%, 65%, 70%, 75%, 80%,    85%, 90%, 91%, 92%, 93%, 94% 95%, 96%, 97%, 98%, 99%, or 100%.

Kits and Compositions Compositions

Disclosed herein are compositions useful for the detection of a genotypeor biomarker in a sample obtained from a subject according to themethods described herein. Aspects disclosed herein provide compositionscomprises a polynucleotide sequence comprising at least 10 but less than50 contiguous nucleotides of any one of SEQ ID NOS: 1-48, or 57-59, orreverse complements thereof, wherein the contiguous polynucleotidesequence comprises a detectable molecule. In some embodiments, thepolynucleotide sequence comprises the nucleobase at a nucleopositionindicated by the non-nucleic acid letter (e.g., S, R, V) in any one ofSEQ ID NOS: 1-48, or 57-59. In various embodiments, the detectablemolecule comprises a fluorophore. In other embodiments, thepolynucleotide sequences further comprise a quencher.

Also disclosed herein are compositions comprising an antibody orantigen-binding fragment that specifically binds to a target proteindescribed herein (e.g., TL1A) wherein the antibody or antigen-bindingfragment comprises a detectable molecule. In various embodiments, theantibody comprises a monoclonal antibody, a chimeric antibody, aCDR-grafted antibody, a Fab, a Fab′, a F(ab′)₂, a Fv, a disulfide linkedFv, a scFv, a single domain antibody, a diabody, a multispecificantibody, a dual specific antibody, an anti-idiotypic antibody, or abispecific antibody. In some embodiments, the antibody orantigen-binding fragment comprises an IgG antibody, an IgM antibody,and/or an IgE antibody. In some embodiments, the detectable moleculecomprises a fluorophore. In some embodiments, the antibody orantigen-binding fragment is conjugated to a paramagnetic particle (e.g.,bead).

Kits

Disclosed herein, are kits useful for to detect the genotypes and/orbiomarkers disclosed herein. In some embodiments, the kits disclosedherein may be used to diagnose and/or treat a disease or condition in asubject; or select a patient for treatment and/or monitor a treatmentdisclosed herein. In some embodiments, the kit comprises thecompositions described herein, which can be used to perform the methodsdescribed herein. Kits comprise an assemblage of materials orcomponents, including at least one of the compositions. Thus, in someembodiments the kit contains a composition including of thepharmaceutical composition, for the treatment of IBD. In otherembodiments, the kits contains all of the components necessary and/orsufficient to perform an assay for detecting and measuring IBD markers,including all controls, directions for performing assays, and anynecessary software for analysis and presentation of results.

In some instances, the kits described herein comprise components fordetecting the presence, absence, and/or quantity of a target nucleicacid and/or protein described herein. In some embodiments, the kitfurther comprises components for detecting the presence, absence, and/orquantity of a serological marker described herein. In some embodiments,the kit comprises the compositions (e.g., primers, probes, antibodies)described herein. The disclosure provides kits suitable for assays suchas enzyme-linked immunosorbent assay (ELISA), single-molecular array(Simoa), PCR, and qPCR. The exact nature of the components configured inthe kit depends on its intended purpose.

In some embodiments, the kits described herein are configured for thepurpose of treating and/or characterizing a disease or condition (e.g.,Crohn's disease), or subclinical phenotype thereof (e.g., structuring,penetrating, or structuring and penetrating disease phenotypes) in asubject. In some embodiments, the kits described herein are configuredfor the purpose of identifying a subject suitable for treatment with aninhibitor of TL1A activity or expression (e.g., anti-TL1A antibody). Insome embodiments, the kit is configured particularly for the purpose oftreating mammalian subjects. In some embodiments, the kit is configuredparticularly for the purpose of treating human subjects. In furtherembodiments, the kit is configured for veterinary applications, treatingsubjects such as, but not limited to, farm animals, domestic animals,and laboratory animals. In some embodiments, the kit is configured toselect a subject for a therapeutic agent, such as those disclosedherein. In some embodiments, the kit is configured to select a subjectfor treatment with a therapeutic agent disclosed herein. An exemplarytherapeutic agent is an anti-TL1A antibody.

Instructions for use may be included in the kit. Optionally, the kitalso contains other useful components, such as, diluents, buffers,pharmaceutically acceptable carriers, syringes, catheters, applicators,pipetting or measuring tools, bandaging materials or other usefulparaphernalia. The materials or components assembled in the kit can beprovided to the practitioner stored in any convenient and suitable waysthat preserve their operability and utility. For example the componentscan be in dissolved, dehydrated, or lyophilized form; they can beprovided at room, refrigerated or frozen temperatures. The componentsare typically contained in suitable packaging material(s). As employedherein, the phrase “packaging material” refers to one or more physicalstructures used to house the contents of the kit, such as compositionsand the like. The packaging material is constructed by well-knownmethods, preferably to provide a sterile, contaminant-free environment.The packaging materials employed in the kit are those customarilyutilized in gene expression assays and in the administration oftreatments. As used herein, the term “package” refers to a suitablesolid matrix or material such as glass, plastic, paper, foil, and thelike, capable of holding the individual kit components. Thus, forexample, a package can be a glass vial or prefilled syringes used tocontain suitable quantities of the pharmaceutical composition. Thepackaging material has an external label which indicates the contentsand/or purpose of the kit and its components.

Systems

Disclosed herein are systems for identifying a subject as being suitablefor treatment with an inhibitor of TL1A activity or expression (e.g.,anti-TL1A antibody). In some embodiments, the systems described hereincomprise kits and compositions for detecting the genotypes describedherein in a biological sample of a subject. The system may comprise acomputer system for implementing one or more methods of the disclosure,such as for example, receiving genotype data of a subject 201, inputtingthe genotype data into an algorithm to produce a TNFSF15 profile 202,and generating a report comprising the TNFSF15 profile of the subject203, and displaying the report to a user on a graphical user interface204, as shown in FIG. 2. A “TNFSF15 profile” as used herein refers to aprofile of expression of one or more genotypes described herein in asubject that is detected in a biological sample obtained from thesubject. In some embodiments, a TNFSF15 profile comprises a positive, anegative, or an indeterminate result (e.g., therapeutic response totreatment with an inhibitor of TL1A activity or expression).

Computer Systems

FIG. 3 shows a computer system 301 that is programmed or otherwiseconfigured to generate a TNFSF15 profile for a subject in need thereof.The computer system 301 canregulate various aspects of producing theTNFSF15 profile (e.g., receiving genotype data, generating a report withthe TNFSF15 profile of the biological sample, and displaying the reportto a user), of the present disclosure, such as, for example, byincluding permissions or encryption of genotype data and/or TNFSF15profile of the subject to ensure patient privacy.

The computer system 301 can be an electronic device of a user or acomputer system that is remotely located with respect to the electronicdevice. The electronic device can be a mobile electronic device, such asa mobile electronic device belonging to a physician.

The computer system 301 includes a central processing unit (CPU, also“processor” and “computer processor” herein) 305, which can be a singlecore or multi core processor, or a plurality of processors for parallelprocessing. The computer system 301 also includes memory or memorylocation 310 (e.g., random-access memory, read-only memory, flashmemory), electronic storage unit 315 (e.g., hard disk), communicationinterface 320 (e.g., network adapter) for communicating with one or moreother systems, and peripheral devices 325, such as cache, other memory,data storage and/or electronic display adapters. The memory 310, storageunit 315, interface 320 and peripheral devices 325 are in communicationwith the CPU 305 through a communication bus (solid lines), such as amotherboard. The storage unit 315 can be a data storage unit (or datarepository) for storing data. The computer system 301 can be operativelycoupled to a computer network (“network”) 330 with the aid of thecommunication interface 320. The network 330 can be the Internet, aninternet and/or extranet, or an intranet and/or extranet that is incommunication with the Internet. The network 330 in some cases is atelecommunication and/or data network. The network 330 can include oneor more computer servers, which can enable distributed computing, suchas cloud computing. The network 330, in some cases with the aid of thecomputer system 301, can implement a peer-to-peer network, which mayenable devices coupled to the computer system 301 to behave as a clientor a server.

The CPU 305 can execute a sequence of machine-readable instructions,which can be embodied in a program or software. The instructions may bestored in a memory location, such as the memory 310. The instructionscan be directed to the CPU 305, which can subsequently program orotherwise configure the CPU 305 to implement methods of the presentdisclosure. Examples of operations performed by the CPU 305 can includefetch, decode, execute, and writeback.

The CPU 305 can be part of a circuit, such as an integrated circuit. Oneor more other components of the system 301 can be included in thecircuit. In some cases, the circuit is an application specificintegrated circuit (ASIC).

The storage unit 315 can store files, such as drivers, libraries andsaved programs. The storage unit 315 can store user data, e.g., userpreferences and user programs. The computer system 301 in some cases caninclude one or more additional data storage units that are external tothe computer system 301, such as located on a remote server that is incommunication with the computer system 301 through an intranet or theInternet.

The computer system 301 can communicate with one or more remote computersystems through the network 330. For instance, the computer system 301can communicate with a remote computer system of a user. Examples ofremote computer systems include personal computers (e.g., portable PC),slate or tablet PC's (e.g., Apple® Wad, Samsung® Galaxy Tab),telephones, Smart phones (e.g., Apple® iPhone, Android-enabled device,Blackberry®), or personal digital assistants. The user can access thecomputer system 301 via the network 330.

Methods as described herein can be implemented by way of machine (e.g.,computer processor) executable code stored on an electronic storagelocation of the computer system 301, such as, for example, on the memory310 or electronic storage unit 315. The machine executable or machinereadable code can be provided in the form of software. During use, thecode can be executed by the processor 305. In some cases, the code canbe retrieved from the storage unit 315 and stored on the memory 310 forready access by the processor 305. In some situations, the electronicstorage unit 315 can be precluded, and machine-executable instructionsare stored on memory 310.

The code can be pre-compiled and configured for use with a machinehaving a processer adapted to execute the code, or can be compiledduring runtime. The code can be supplied in a programming language thatcan be selected to enable the code to execute in a pre-compiled oras-compiled fashion.

Aspects of the systems and methods provided herein, such as the computersystem 301, can be embodied in programming. Various aspects of thetechnology may be thought of as “products” or “articles of manufacture”typically in the form of machine (or processor) executable code and/orassociated data that is carried on or embodied in a type of machinereadable medium. Machine-executable code can be stored on an electronicstorage unit, such as memory (e.g., read-only memory, random-accessmemory, flash memory) or a hard disk. “Storage” type media can includeany or all of the tangible memory of the computers, processors or thelike, or associated modules thereof, such as various semiconductormemories, tape drives, disk drives and the like, which may providenon-transitory storage at any time for the software programming. All orportions of the software may at times be communicated through theInternet or various other telecommunication networks. Suchcommunications, for example, may enable loading of the software from onecomputer or processor into another, for example, from a managementserver or host computer into the computer platform of an applicationserver. Thus, another type of media that may bear the software elementsincludes optical, electrical and electromagnetic waves, such as usedacross physical interfaces between local devices, through wired andoptical landline networks and over various air-links. The physicalelements that carry such waves, such as wired or wireless links, opticallinks or the like, also may be considered as media bearing the software.As used herein, unless restricted to non-transitory, tangible “storage”media, terms such as computer or machine “readable medium” refer to anymedium that participates in providing instructions to a processor forexecution.

Hence, a machine readable medium, such as computer-executable code, maytake many forms, including but not limited to, a tangible storagemedium, a carrier wave medium or physical transmission medium.Non-volatile storage media include, for example, optical or magneticdisks, such as any of the storage devices in any computer(s) or thelike, such as may be used to implement the databases, etc. shown in thedrawings. Volatile storage media include dynamic memory, such as mainmemory of such a computer platform. Tangible transmission media includecoaxial cables; copper wire and fiber optics, including the wires thatcomprise a bus within a computer system. Carrier-wave transmission mediamay take the form of electric or electromagnetic signals, or acoustic orlight waves such as those generated during radio frequency (RF) andinfrared (IR) data communications. Common forms of computer-readablemedia therefore include for example: a floppy disk, a flexible disk,hard disk, magnetic tape, any other magnetic medium, a CD-ROM, DVD orDVD-ROM, any other optical medium, punch cards paper tape, any otherphysical storage medium with patterns of holes, a RAM, a ROM, a PROM andEPROM, a FLASH-EPROM, any other memory chip or cartridge, a carrier wavetransporting data or instructions, cables or links transporting such acarrier wave, or any other medium from which a computer may readprogramming code and/or data. Many of these forms of computer readablemedia may be involved in carrying one or more sequences of one or moreinstructions to a processor for execution.

The computer system 301 can include or be in communication with anelectronic display 335 that comprises a user interface (UI) 340 forproviding, for example, a report comprising the TNFSF15 profile of thesubject or other relevant clinical information for purposes of informinga selection of a therapeutic agent (e.g., anti-TL1A antibody) to treat adisease or condition of the subject described herein. Examples of UI'sinclude, without limitation, a graphical user interface (GUI) andweb-based user interface.

Methods and systems of the present disclosure can be implemented by wayof one or more algorithms. An algorithm can be implemented by way ofsoftware upon execution by the central processing unit 305. Thealgorithm can, for example, perform: (a) receiving genotype data of asubject 401, (b) determining whether the genotypes are heterozygous orhomozygous for at least three polymorphisms 402, (c) generating anoutcome using predetermined parameters 403, and (d) displaying theoutcome to a user (e.g., physician) on a user interface of an electronicdevice 404, as shown in FIG. 4. In some embodiments, the outcome ispositive, negative or indeterminant. In some embodiments, thepredetermined parameters are genotype combinations known to bepredictive of a therapeutic response to a treatment, such as with aninhibitor of TL1A activity or expression.

Web Application

In some embodiments, the computer system comprises software for a webapplication. In light of the disclosure provided herein, those of skillin the art will recognize that a web application may utilize one or moresoftware frameworks and one or more database systems. A web application,for example, is created upon a software framework such as Microsoft®.NETor Ruby on Rails (RoR). A web application, in some instances, utilizesone or more database systems including, by way of non-limiting examples,relational, non-relational, feature oriented, associative, and XMLdatabase systems. Suitable relational database systems include, by wayof non-limiting examples, Microsoft SQL Server, mySQL™, and Oracle®.Those of skill in the art will also recognize that a web application maybe written in one or more versions of one or more languages. In someembodiments, a web application is written in one or more markuplanguages, presentation definition languages, client-side scriptinglanguages, server-side coding languages, database query languages, orcombinations thereof. In some embodiments, a web application is writtento some extent in a markup language such as Hypertext Markup Language(HTML), Extensible Hypertext Markup Language (XHTML), or eXtensibleMarkup Language (XML). In some embodiments, a web application is writtento some extent in a presentation definition language such as CascadingStyle Sheets (CSS). In some embodiments, a web application is written tosome extent in a client-side scripting language such as AsynchronousJavascript and XML (AJAX), Flash® Actionscript, Javascript, orSilverlight®. In some embodiments, a web application is written to someextent in a server-side coding language such as Active Server Pages(ASP), ColdFusion®, Perl, Java™, JavaServer Pages (JSP), HypertextPreprocessor (PHP), Python™, Ruby, Tcl, Smalltalk, WebDNA®, or Groovy.In some embodiments, a web application is written to some extent in adatabase query language such as Structured Query Language (SQL). A webapplication may integrate enterprise server products such as IBM® LotusDomino®. A web application may include a media player element. A mediaplayer element may utilize one or more of many suitable multimediatechnologies including, by way of non-limiting examples, Adobe® Flash®,HTML 5, Apple® QuickTime®, Microsoft® Silverlight®, Java™, and Unity®.

Mobile Application

In some embodiments, the computer system comprises software for a mobileapplication. The mobile application may be provided to a mobile digitalprocessing device at the time it is manufactured. The mobile applicationmay be provided to a mobile digital processing device via the computernetwork described herein.

A mobile application is created by techniques known to those of skill inthe art using hardware, languages, and development environments known tothe art. Those of skill in the art will recognize that mobileapplications may be written in several languages. Suitable programminglanguages include, by way of non-limiting examples, C, C++, C#,Featureive-C, Java™, Javascript, Pascal, Feature Pascal, Python™, Ruby,VB.NET, WML, and XHTML/HTML with or without CSS, or combinationsthereof.

Suitable mobile application development environments are available fromseveral sources. Commercially available development environmentsinclude, by way of non-limiting examples, AirplaySDK, alcheMo,Appcelerator®, Celsius, Bedrock, Flash Lite, NET Compact Framework,Rhomobile, and WorkLight Mobile Platform. Other development environmentsmay be available without cost including, by way of non-limitingexamples, Lazarus, MobiFlex, MoSync, and Phonegap. Also, mobile devicemanufacturers distribute software developer kits including, by way ofnon-limiting examples, iPhone and iPad (iOS) SDK, Android™ SDK,BlackBerry® SDK, BREW SDK, Palm® OS SDK, Symbian SDK, webOS SDK, andWindows® Mobile SDK.

Those of skill in the art will recognize that several commercial forumsare available for distribution of mobile applications including, by wayof non-limiting examples, Apple® App Store, Android™ Market, BlackBerry®App World, App Store for Palm devices, App Catalog for webOS, Windows®Marketplace for Mobile, Ovi Store for Nokia® devices, Samsung® Apps, andNintendo® DSi Shop.

Standalone Application

In some embodiments, the computer system comprises software a standaloneapplication, which is a program that may be run as an independentcomputer process, not an add-on to an existing process, e.g., not aplug-in. Those of skill in the art will recognize that standaloneapplications are sometimes compiled. In some instances, a compiler is acomputer program(s) that transforms source code written in a programminglanguage into binary feature code such as assembly language or machinecode. Suitable compiled programming languages include, by way ofnon-limiting examples, C, C++, Featureive-C, COBOL, Delphi, Eiffel,Java™, Lisp, Python™, Visual Basic, and VB NET, or combinations thereof.Compilation may be often performed, at least in part, to create anexecutable program. In some instances, a computer program includes oneor more executable complied applications.

Web Browser Plug-in

In some embodiments, the computer system comprises software thatcomprises a web browser plug-in. In computing, a plug-in, in someinstances, is one or more software components that add specificfunctionality to a larger software application. Makers of softwareapplications may support plug-ins to enable third-party developers tocreate abilities which extend an application, to support easily addingnew features, and to reduce the size of an application. When supported,plug-ins enable customizing the functionality of a software application.For example, plug-ins are commonly used in web browsers to play video,generate interactivity, scan for viruses, and display particular filetypes. Those of skill in the art will be familiar with several webbrowser plug-ins including, Adobe® Flash® Player, Microsoft®Silverlight®, and Apple® QuickTime®. The toolbar may comprise one ormore web browser extensions, add-ins, or add-ons. The toolbar maycomprise one or more explorer bars, tool bands, or desk bands.

In view of the disclosure provided herein, those of skill in the artwill recognize that several plug-in frameworks are available that enabledevelopment of plug-ins in various programming languages, including, byway of non-limiting examples, C++, Delphi, Java™ PHP, Python™, and VB.NET, or combinations thereof.

In some embodiments, Web browsers (also called Internet browsers) aresoftware applications, designed for use with network-connected digitalprocessing devices, for retrieving, presenting, and traversinginformation resources on the World Wide Web. Suitable web browsersinclude, by way of non-limiting examples, Microsoft Internet Explorer®,Mozilla® Firefox®, Google® Chrome, Apple® Safari®, Opera Software®Opera®, and KDE Konqueror. The web browser, in some instances, is amobile web browser. Mobile web browsers (also called microbrowsers,mini-browsers, and wireless browsers) may be designed for use on mobiledigital processing devices including, by way of non-limiting examples,handheld computers, tablet computers, netbook computers, subnotebookcomputers, smartphones, music players, personal digital assistants(PDAs), and handheld video game systems. Suitable mobile web browsersinclude, by way of non-limiting examples, Google® Android® browser, RIMBlackBerry® Browser, Apple® Safari®, Palm® Blazer, Palm® WebOS® Browser,Mozilla® Firefox® for mobile, Microsoft® Internet Explorer® Mobile,Amazon® Kindle® Basic Web, Nokia® Browser, Opera Software® Opera®Mobile, and Sony® PSP™ browser.

Software Modules

The medium, method, and system disclosed herein comprise one or moresoftwares, servers, and database modules, or use of the same. In view ofthe disclosure provided herein, software modules may be created bytechniques known to those of skill in the art using machines, software,and languages known to the art. The software modules disclosed hereinmay be implemented in a multitude of ways. In some embodiments, asoftware module comprises a file, a section of code, a programmingfeature, a programming structure, or combinations thereof. A softwaremodule may comprise a plurality of files, a plurality of sections ofcode, a plurality of programming features, a plurality of programmingstructures, or combinations thereof. By way of non-limiting examples,the one or more software modules comprise a web application, a mobileapplication, and/or a standalone application. Software modules may be inone computer program or application. Software modules may be in morethan one computer program or application. Software modules may be hostedon one machine. Software modules may be hosted on more than one machine.Software modules may be hosted on cloud computing platforms. Softwaremodules may be hosted on one or more machines in one location. Softwaremodules may be hosted on one or more machines in more than one location.

Databases

The medium, method, and system disclosed herein comprise one or moredatabases, or use of the same. In view of the disclosure providedherein, those of skill in the art will recognize that many databases aresuitable for storage and retrieval of geologic profile, operatoractivities, division of interest, and/or contact information of royaltyowners. Suitable databases include, by way of non-limiting examples,relational databases, non-relational databases, feature orienteddatabases, feature databases, entity-relationship model databases,associative databases, and XML databases. In some embodiments, adatabase is internet-based. In some embodiments, a database isweb-based. In some embodiments, a database is cloud computing-based. Adatabase may be based on one or more local computer storage devices.

Data Transmission

The subject matter described herein, including methods for producing aTNFSF15 profile are configured to be performed in one or more facilitiesat one or more locations. Facility locations are not limited by countryand include any country or territory. In some instances, one or moresteps are performed in a different country than another step of themethod. In some instances, one or more steps for obtaining a sample areperformed in a different country than one or more steps for detectingthe presence or absence of a genotype in a biological sample. In someembodiments, one or more method steps involving a computer system areperformed in a different country than another step of the methodsprovided herein. In some embodiments, data processing and analyses areperformed in a different country or location than one or more steps ofthe methods described herein. In some embodiments, one or more articles,products, or data are transferred from one or more of the facilities toone or more different facilities for analysis or further analysis. Anarticle includes, but is not limited to, one or more components obtainedfrom a subject, e.g., processed cellular material. Processed cellularmaterial includes, but is not limited to, cDNA reverse transcribed fromRNA, amplified RNA, amplified cDNA, sequenced DNA, isolated and/orpurified RNA, isolated and/or purified DNA, and isolated and/or purifiedpolypeptide. Data includes, but is not limited to, information regardingthe stratification of a subject, and any data produced by the methodsdisclosed herein. In some embodiments of the methods and systemsdescribed herein, the analysis is performed and a subsequent datatransmission step will convey or transmit the results of the analysis.

In some embodiments, any step of any method described herein isperformed by a software program or module on a computer. In additionalor further embodiments, data from any step of any method describedherein is transferred to and from facilities located within the same ordifferent countries, including analysis performed in one facility in aparticular location and the data shipped to another location or directlyto an individual in the same or a different country. In additional orfurther embodiments, data from any step of any method described hereinis transferred to and/or received from a facility located within thesame or different countries, including analysis of a data input, such asgenetic or processed cellular material, performed in one facility in aparticular location and corresponding data transmitted to anotherlocation, or directly to an individual, such as data related to thediagnosis, prognosis, responsiveness to therapy (e.g., anti-TL1Atherapy), or the like, in the same or different location or country.

Business Methods Utilizing a Computer

The methods described herein may utilize one or more computers. Thecomputer may be used for managing customer and biological sampleinformation such as sample or customer tracking, database management,analyzing molecular profiling data, analyzing cytological data, storingdata, billing, marketing, reporting results, storing results, or acombination thereof. The computer may include a monitor or other userinterface for displaying data, results, billing information, marketinginformation (e.g. demographics), customer information, or sampleinformation. The computer may also include means for data or informationinput. The computer may include a processing unit and fixed or removablemedia or a combination thereof. The computer may be accessed by a userin physical proximity to the computer, for example via a keyboard and/ormouse, or by a user that does not necessarily have access to thephysical computer through a communication medium such as a modem, aninternet connection, a telephone connection, or a wired or wirelesscommunication signal carrier wave. In some cases, the computer may beconnected to a server or other communication device for relayinginformation from a user to the computer or from the computer to a user.In some cases, the user may store data or information obtained from thecomputer through a communication medium on media, such as removablemedia. It is envisioned that data relating to the methods can betransmitted over such networks or connections for reception and/orreview by a party. The receiving party can be but is not limited to anindividual, a health care provider (e.g., physician) or a health caremanager. In one embodiment, a computer-readable medium includes a mediumsuitable for transmission of a result of an analysis of a biologicalsample, such as exosome bio-signatures. The medium can include a resultregarding an exosome bio-signature of a subject, wherein such a resultis derived using the methods described herein.

The entity obtaining a report with the TNFSF15 profile may enterbiological sample information into a database for the purpose of one ormore of the following: inventory tracking, assay result tracking, ordertracking, customer management, customer service, billing, and sales.Sample information may include, but is not limited to: customer name,unique customer identification, customer associated medicalprofessional, indicated assay or assays, assay results, adequacy status,indicated adequacy tests, medical history of the individual, preliminarydiagnosis, suspected diagnosis, sample history, insurance provider,medical provider, third party testing center or any information suitablefor storage in a database. Sample history may include but is not limitedto: age of the sample, type of sample, method of acquisition, method ofstorage, or method of transport.

The database may be accessible by a customer, medical professional,insurance provider, or other third party. Database access may take theform of electronic communication such as a computer or telephone. Thedatabase may be accessed through an intermediary such as a customerservice representative, business representative, consultant, independenttesting center, or medical professional. The availability or degree ofdatabase access or sample information, such as assay results, may changeupon payment of a fee for products and services rendered or to berendered. The degree of database access or sample information may berestricted to comply with generally accepted or legal requirements forpatient or customer confidentiality.

II. Exemplary Embodiments

Among the exemplary embodiments are:

-   1. A computer system for evaluating a sample from a subject, the    system comprising:    -   a) a central computing environment;    -   b) an input device operatively connected to said central        computing environment, wherein said input device is configured        to receive a presence or absence of a genotype that correlates        with a disease state in the sample;    -   c) a trained algorithm executed by said central computing        environment, wherein the trained algorithm is configured to use        the presence or absence of the genotype to classify said sample        as at least one of (i) a disease or normal sample, and (ii) a        response or a non-response to an anti-TL1A therapy; and    -   d) an output device operatively connected to said central        computing environment, wherein said output device is configured        to provide information on the classification to a user.-   2. The computer system of embodiment 1, wherein the disease state    comprises at least one of an inflammatory, a fibrostenotic, and a    fibrotic, disease or condition.-   3. The computer system of embodiment 1 or embodiment 2, wherein the    disease state is a TL1A mediated disease state selected from the    group consisting of inflammatory bowel disease (IBD), Crohn's    disease (CD), obstructive CD, ulcerative colitis (UC), intestinal    fibrosis, intestinal fibrostenosis, rheumatoid arthritis, and    primary sclerosing cholangitis.-   4. The computer system of any previous embodiment, wherein the    sample comprises whole blood, plasma, serum, or tissue.-   5. The computer system of any previous embodiment, wherein the    genotype comprises at least one polymorphism selected from Table 1    or Table 4, a polymorphism in linkage disequilibrium (LD) therewith,    and any combination thereof.-   6. The computer system of any previous embodiment, wherein the    genotype comprises at least one polymorphism comprising a    non-reference allele.-   7. The computer system of any previous embodiment, wherein the    genotype comprises at least two polymorphisms provided in Table 1 or    Table 4.-   8. The computer system of any previous embodiment, wherein the    genotype comprises at least three polymorphisms provided in Table 1    or Table 4.-   9. The computer system of any previous embodiment, further    comprising the genotype is homozygous.-   10. The computer system of embodiment 5-9, where LD is defined by an    r² value of at least 0.80, 0.85, 0.90, 0.95, or 1.0.-   11. The computer system of any previous embodiment, wherein the    genotype is associated with a risk that a subject has, or will    develop, the disease state by a P value of at most about 1.0×10⁻⁶,    about 1.0×10⁻⁷, about 1.0×10⁻¹, about 1.0×10⁻⁹, about 1.0×10⁻¹⁰,    about 1.0×10⁻²⁰, about 1.0×10⁻³⁰, about 1.0×10⁻⁴⁰, about 1.0×10⁻⁵⁰,    about 1.0×10⁻⁶⁰, about 1.0×10⁻⁷⁰, about 1.0×10⁻⁸⁰, about 1.0×10⁻⁹⁰,    or about 1.0×10⁻¹⁰⁰.-   12. The computer system of any previous embodiment, wherein said    output device provides a report summarizing said information on said    classification.-   13. The computer system of any previous embodiment, wherein said    report comprises a recommendation for treatment of said disease    state.-   14. The computer system of embodiment 13, wherein the treatment    comprises administration of an inhibitor of TL1A activity or    expression.-   15. The computer system of embodiment 14, wherein the inhibitor of    TL1A activity or expression comprises an antibody or antigen-binding    fragment, peptide, or small molecule.-   16. The computer system of any preceding embodiment, wherein said    genotype is determined with an assay comprising polymerase chain    reaction (PCR), quantitative reverse-transcription PCR (qPCR),    automated sequencing, genotype array, or a combination thereof.-   17. Use of a composition comprising one or more binding agents for    generating a report that classifies a sample from a subject as at    least one of (i) a disease or non-disease state and (ii) a response    or a non-response to an anti-TL1A therapy, wherein the one or more    binding agents specifically bind to a risk allele provided in Table    1 corresponding to a polymorphism provided in Table 1, their    compliment, a polymorphism in linkage disequilibrium therewith, and    any combination thereof.-   18. The use of embodiment 17, wherein generating the report further    comprises:    -   a) providing the sample from the subject;    -   b) assaying the sample from the subject for detecting the        presence of the risk allele corresponding to the polymorphism        provided in Table 1;    -   c) generating the report based on the result of step (b); and    -   d) determining whether said subject has or is likely to exhibit        a positive therapeutic response to a treatment with an inhibitor        of TL1A activity or expression based on the results of step (b).-   19. The use of embodiment 17 or 18, wherein the disease state    comprises at least one of an inflammatory, a fibrostenotic, and a    fibrotic, disease or condition.-   20. The use of embodiment 17-19, wherein the disease state is a    TL1A-mediated disease state selected from the group consisting of    inflammatory bowel disease (IBD), Crohn's disease (CD), obstructive    CD, ulcerative colitis (UC), intestinal fibrosis, intestinal    fibrostenosis, and primary sclerosing cholangitis.-   21. The use of any of embodiments 17-20, wherein the sample    comprises whole blood, plasma, serum, or tissue.-   22. The use of embodiment 18, wherein assaying the sample from the    subject for detecting the presence of the risk allele corresponding    to the polymorphism provided in Table 1 of step (b) comprises:    -   a) contacting the sample with the one or more binding agents        that specifically bind to at least 10 contiguous nucleobases        that includes the risk allele provided in any one of SEQ ID NOS:        1-41, or 57-59; and    -   b) determining whether the sample specifically binds to said one        or more binding agents, wherein binding of the sample to the one        or more binding agents indicates the presence of the        polymorphism in the subject.-   23. The use of embodiment 18, wherein assaying the sample from the    subject for detecting the presence of the risk allele corresponding    to the polymorphism provided in Table 1 of step (b) comprises    sequencing of the sample.-   24. The use of embodiment 18, wherein assaying the sample from the    subject for detecting the presence of the one or more polymorphisms    of step (b) comprises quantifying the amount of DNA comprising the    risk allele.-   25. The use of embodiment 24, wherein the quantifying comprises PCR.-   26. The use of embodiment 25, wherein the PCR comprises real-time    PCR.-   27. The use of embodiment 24, wherein the quantifying comprises    hybridization.-   28. A composition comprising one or more binding agents that    specifically bind to a risk allele corresponding to a polymorphism    provided in Table 1, wherein the one or more binding agents are    selected to classify a sample as at least one of (i) a disease or    non-disease or a disease state and (ii) a response or a non-response    to an anti-TL1A therapy.-   29. The composition of embodiment 28, wherein the one or more    binding agents comprise oligonucleotides.-   30. The composition of embodiment 29, wherein the oligonucleotides    comprise RNA or DNA.-   31. The composition of embodiment 29, wherein the one or more    binding agents comprise aptamers, antibodies, peptide nucleic acids,    or pyranosyl RNA.-   32. A kit for detecting at least one of an inflammatory, a    fibrostenotic, and a fibrotic, disease or condition in a subject,    the kit comprising:    -   a) at least one binding agent that specifically binds to at        least 10 contiguous nucleic acid molecules provided in any one        of SEQ ID NOS: 1-41, or 57-59 including a corresponding risk        allele provided in Table 1, or their complement, wherein the at        least one binding agent is selected to detect at least one        of (i) a disease or non-disease state and (ii) a response or a        non-response to an anti-TL1A therapy; and    -   b) reagents for detecting binding of said at least one binding        agent to a DNA sample from a subject.-   33. The kit of embodiment 32, wherein the at least one binding agent    comprises at least one oligonucleotide.-   34. The kit of embodiment 32, wherein the at least one binding agent    comprises at least one aptamer, antibody, peptide nucleic acid, or    pyranosyl RNA.-   35. The kit of embodiment 32-34, wherein the at least one binding    agent is labelled with a detectable label.-   36. The kit of embodiment 32-35 wherein the at least one binding    agent is immobilized to a surface.-   37. A system for generating a report that classifies a sample a    disease or non-disease of a disease state, comprising:    -   a) a computer system that:        -   i. generates a molecular profile of a DNA sample based upon            the presence of at least one polymorphism, or their            complement; and        -   ii. generates a report that classifies the sample based on            said molecular profile; and    -   b) a computer screen that displays said report.-   38. The system of embodiment 37, wherein the presence of the at    least one polymorphism is based on the result of an assay of said    DNA sample, which result is entered into a database.-   39. The system of embodiment 37-38, further comprising an input for    said result.-   40. The system of claim 37-39, wherein the at least one polymorphism    is selected from Table 1.-   41. The system of claim 37-41, wherein the at least one polymorphism    comprises a non-reference allele.-   42. The system of claim 41, wherein the at least one polymorphism is    two polymorphisms.-   43. The system of claim 41, wherein the at least one polymorphism is    three polymorphisms.-   44. Use of a composition comprising an inhibitor of TL1A for    treating a subject, provided the subject is a carrier of a genotype    comprising a polymorphism provided in Table 1 or Table 4.-   45. The use of embodiment 44, wherein the inhibitor of TL1A activity    or expression is an anti-TL1A antibody.-   46. The use of embodiment 45, wherein the anti-TL1A antibody is    selected from Table 2B.-   47. The use of embodiment 45, wherein the anti-TL1A antibody    comprises an amino acid sequence provided in Table 2A.-   48. The use of embodiment 45, wherein the anti-TL1A antibody binds    to the same region of human TL1A as a reference antibody selected    from Table 2B.-   49. The use of embodiment 45, wherein the anti-TL1A antibody binds    to the same region of human TL1A as a reference antibody, the    reference antibody comprising an amino acid sequence provided in    Table 2A.-   50. The use of embodiments 45-49, wherein the anti-TL1A antibody is    a neutralizing TL1A antibody.-   51. The use of embodiments 45-49, wherein the anti-TL1A antibody is    an antagonist of TL1A.-   52. The use of embodiments 44-51, wherein the genotype comprises at    least two polymorphisms provided in Table 2 or Table 4.-   53. The use of embodiments 44-51, wherein the genotype comprises at    least three polymorphisms provided in Table 2 or Table 4.-   54. The method of use of embodiments 44-53, wherein the genotype    comprises at least one polymorphism comprising a non-reference    allele.-   55. The computer system of embodiments 1-16, wherein said trained    algorithm is configured to classify said sample as a positive    therapeutic response to the anti-TL1A therapy with a positive    predictive value of at least or about 50%, 55%, 60%, 65%, 70%, 75%,    80%, 85%, 90%, 91%, 92%, 93%, 94% 95%, 96%, 97%, 98%, 99%, or 100%.-   56. The computer system of embodiments 1-16, wherein said trained    algorithm is configured to classify said sample as a positive    therapeutic response to the anti-TL1A therapy with a specificity of    at least or about 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%,    92%, 93%, 94% 95%, 96%, 97%, 98%, 99%, or 100%.-   57. The use of embodiments 17-27, wherein the report classifies the    sample as a positive therapeutic response to the anti-TL1A therapy    with a positive predictive value of at least or about 50%, 55%, 60%,    65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% 95%, 96%, 97%, 98%,    99%, or 100%.-   58. The use of embodiments 17-27, wherein the report classifies the    sample as a positive therapeutic response to the anti-TL1A therapy    with a specificity of at least or about 50%, 55%, 60%, 65%, 70%,    75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% 95%, 96%, 97%, 98%, 99%, or    100%.-   59. The system of embodiments 37-43, wherein the report that    classifies the sample based on said molecular profile as positive    for a therapeutic response to a treatment with an anti-TL1A therapy    with a positive predictive value of at least or about 50%, 55%, 60%,    65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% 95%, 96%, 97%, 98%,    99%, or 100%.-   60. The system of embodiments 37-43, wherein the report that    classifies the sample based on said molecular profile as positive    for a therapeutic response to a treatment with an anti-TL1A therapy    with a specificity of at least or about 50%, 55%, 60%, 65%, 70%,    75%, 80%, 85%, 90%, 91%, 92%, 93%, 94% 95%, 96%, 97%, 98%, 99%, or    100%.

Definitions

Unless defined otherwise, all terms of art, notations and othertechnical and scientific terms or terminology used herein are intendedto have the same meaning as is commonly understood by one of ordinaryskill in the art to which the claimed subject matter pertains. In somecases, terms with commonly understood meanings are defined herein forclarity and/or for ready reference, and the inclusion of suchdefinitions herein should not necessarily be construed to represent asubstantial difference over what is generally understood in the art.

Throughout this application, various embodiments may be presented in arange format. It should be understood that the description in rangeformat is merely for convenience and brevity and should not be construedas an inflexible limitation on the scope of the disclosure. Accordingly,the description of a range should be considered to have specificallydisclosed all the possible subranges as well as individual numericalvalues within that range. For example, description of a range such asfrom 1 to 6 should be considered to have specifically disclosedsubranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4,from 2 to 6, from 3 to 6 etc., as well as individual numbers within thatrange, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of thebreadth of the range.

As used in the specification and claims, the singular forms “a”, “an”and “the” include plural references unless the context clearly dictatesotherwise. For example, the term “a sample” includes a plurality ofsamples, including mixtures thereof.

The terms “determining,” “measuring,” “evaluating,” “assessing,”“assaying,” and “analyzing” are often used interchangeably herein torefer to forms of measurement. The terms include determining if anelement is present or not (for example, detection). These terms caninclude quantitative, qualitative or quantitative and qualitativedeterminations. Assessing can be relative or absolute. “Detecting thepresence of” can include determining the amount of something present inaddition to determining whether it is present or absent depending on thecontext.

The term “in vivo” is used to describe an event that takes place in asubject's body.

The term “ex vivo” is used to describe an event that takes place outsideof a subject's body. An ex vivo assay is not performed on a subject.Rather, it is performed upon a sample separate from a subject. Anexample of an ex vivo assay performed on a sample is an “in vitro”assay.

The term “in vitro” is used to describe an event that takes placescontained in a container for holding laboratory reagent such that it isseparated from the biological source from which the material isobtained. In vitro assays can encompass cell-based assays in whichliving or dead cells are employed. In vitro assays can also encompass acell-free assay in which no intact cells are employed.

As used herein, the term “about” a number refers to that number plus orminus 10% of that number. The term “about” a range refers to that rangeminus 10% of its lowest value and plus 10% of its greatest value.

As used herein, the terms “homologous,” “homology,” or “percenthomology” when used herein to describe to an amino acid sequence or anucleic acid sequence, relative to a reference sequence, can bedetermined using the formula described by Karlin and Altschul (Proc.Natl. Acad. Sci. USA 87: 2264-2268, 1990, modified as in Proc. Natl.Acad. Sci. USA 90:5873-5877, 1993). Such a formula is incorporated intothe basic local alignment search tool (BLAST) programs of Altschul etal. (J Mol Biol. 1990 Oct. 5; 215(3):403-10; Nucleic Acids Res. 1997Sep. 1; 25(17):3389-402). Percent homology of sequences can bedetermined using the most recent version of BLAST, as of the filing dateof this application. Percent identity of sequences can be determinedusing the most recent version of BLAST, as of the filing date of thisapplication.

The terms “increased,” or “increase” are used herein to generally meanan increase by a statically significant amount. In some embodiments, theterms “increased,” or “increase,” mean an increase of at least 10% ascompared to a reference level, for example an increase of at least about10%, at least about 20%, or at least about 30%, or at least about 40%,or at least about 50%, or at least about 60%, or at least about 70%, orat least about 80%, or at least about 90% or up to and including a 100%increase or any increase between 10-100% as compared to a referencelevel, standard, or control. Other examples of “increase” include anincrease of at least 2-fold, at least 5-fold, at least 10-fold, at least20-fold, at least 50-fold, at least 100-fold, at least 1000-fold or moreas compared to a reference level. An increase can be an absolute amount(e.g., level of protein expression), or a rate of production (e.g., rateof protein expression between two points in time).

The terms, “decreased” or “decrease” are used herein generally to mean adecrease by a statistically significant amount. In some embodiments,“decreased” or “decrease” means a reduction by at least 10% as comparedto a reference level, for example a decrease by at least about 20%, orat least about 30%, or at least about 40%, or at least about 50%, or atleast about 60%, or at least about 70%, or at least about 80%, or atleast about 90% or up to and including a 100% decrease (e.g., absentlevel or non-detectable level as compared to a reference level), or anydecrease between 10-100% as compared to a reference level. In thecontext of a marker or symptom, by these terms is meant a statisticallysignificant decrease in such level. The decrease can be, for example, atleast 10%, at least 20%, at least 30%, at least 40% or more, and ispreferably down to a level accepted as within the range of normal for anindividual without a given disease.

The terms “subject” encompass mammals. Non-limiting examples of mammalinclude, any member of the mammalian class: humans, non-human primatessuch as chimpanzees, and other apes and monkey species; farm animalssuch as cattle, horses, sheep, goats, swine; domestic animals such asrabbits, dogs, and cats; laboratory animals including rodents, such asrats, mice and guinea pigs, and the like. In one aspect, the mammal is ahuman. The term “animal” as used herein comprises human beings andnon-human animals. In one embodiment, a “non-human animal” is a mammal,for example a rodent such as rat or a mouse. In some instances, a humansubject is a “patient,” which as used herein, refers to a subject whomay be diagnosed with a disease or condition disclosed herein.

The term “gene,” as used herein, refers to a segment of nucleic acidthat encodes an individual protein or RNA (also referred to as a “codingsequence” or “coding region”), optionally together with associatedregulatory region such as promoter, operator, terminator and the like,which may be located upstream or downstream of the coding sequence. A“genetic locus” referred to herein, is a particular location within agene.

The term, “genotype” as disclosed herein, refers to the chemicalcomposition of polynucleotide sequences within the genome of anindividual. In some embodiments, the genotype comprises a singlenucleotide polymorphism (SNP) or and indel (insertion or deletion, of anucleobase within a polynucleotide sequence). In some embodiments, agenotype for a particular SNP, or indel is heterozygous. In someembodiments, a genotype for a particular SNP, or indel is homozygous.

A “polymorphism” as used herein refers to an aberration in (e.g., amutation), or of (e.g., insertion/deletion), a nucleic acid sequence, ascompared to the nucleic acid sequence in a reference population. In someembodiments, the polymorphism is common in the reference population. Insome embodiments, the polymorphism is rare in the reference population.In some embodiments, the polymorphism is a single nucleotidepolymorphism.

The term, “single nucleotide polymorphism” or SNP as disclosed herein,refers to a variation in a single nucleotide within a polynucleotidesequence. The term should not be interpreted as placing a restriction ona frequency of the SNP in a given population. The variation of an SNPmay have multiple different forms. A single form of an SNP is referredto as an “allele.” An SNP can be mono-, bi-, tri, or tetra-allelic. ASNP may include a “risk allele,” a “protective allele,” or neither. Byway of example, a reference polynucleotide sequence reading 5′ to 3′ isTTACG. A SNP at allele position 3 (of 5′-TTACG-3′) comprise asubstitution of the reference allele, “A” to a non-reference allele,“C.” If the “C” allele of the SNP is associated with an increasedprobability of developing a phenotypic trait, the allele is considered a“risk” allele. However, the same SNP may also comprise a substitution ofthe “A” allele to a “T” allele at position 3. If the T allele of the SNPis associated with a decreased probability of developing a phenotypictrait, the allele is considered a “protective” allele. The SNP may beobserved in at least 1% of a given population. In some embodiments, theSNP is represented by an “rs” number, which refers to the accession ofreference cluster of one more submitted SNPs in the dbSNP bioinformaticsdatabase as of the filing date of this patent application, and which isincluded within a sequence that comprises the total number ofnucleobases from 5′ to 3′. In some embodiments, a SNP may be furtherdefined by the position of the SNP (nucleobase) within the dbSNPsequence, the position of which is always with reference to 5′ length ofthe sequence plus 1. In some embodiments, a SNP is defined as thegenomic position in a reference genome and the allele change (e.g.chromosome 7 at position 234,123,567 from G allele to A allele in thereference human genome build 37). In some embodiments, the SNV isdefined as the genomic position identified with [brackets] or an “N” ina sequence disclosed herein.

The term, “indel,” as disclosed herein, refers to an insertion, or adeletion, of a nucleobase within a polynucleotide sequence. An indel canbe mono-, bi-, tri, or tetra-allelic. An indel may be “risk,” a“protective,” or neither, for a phenotypic trait. In some embodiments,the indel is represented by an “rs” number, which refers to theaccession of reference cluster of one more submitted indels in the dbSNPbioinformatics database as of the filing date of this patentapplication, and which is included in a sequence that comprises thetotal number of nucleobases from 5′ to 3′. In some embodiments, an indelmay be further defined by the position of the insertion/deletion withinthe dbSNP sequence, the position of which is always with reference tothe 5′ length of the sequence plus 1. In some embodiments, an indel isdefined as the genomic position in a reference genome and the allelechange. In some embodiments, the indel is defined as the genomicposition identified with [brackets] or an “N” in a sequence disclosedherein.

“Haplotype” as used herein, encompasses a group of one or moregenotypes, which tend to be inherited together in a referencepopulation. In some embodiments, a haplotype comprises particularpolymorphism or another polymorphism in linkage disequilibrium (LD)therewith.

“Linkage disequilibrium,” or “LD,” as used herein refers to thenon-random association of alleles or indels in different gene loci in agiven population. LD may be defined by a D′ value corresponding to thedifference between an observed and expected allele or indel frequenciesin the population (D=Pab-PaPb), which is scaled by the theoreticalmaximum value of D. LD may be defined by an r² value corresponding tothe difference between an observed and expected unit of risk frequenciesin the population (D=Pab-PaPb), which is scaled by the individualfrequencies of the different loci. In some embodiments, D′ comprises atleast 0.20. In some embodiments, r² comprises at least 0.70.

The term “medically refractory,” or “refractory,” as used herein, refersto the failure of a standard treatment to induce remission of a disease.In some embodiments, the disease comprises an inflammatory diseasedisclosed herein. A non-limiting example of refractory inflammatorydisease includes refractory Crohn's disease, and refractory ulcerativecolitis (e.g., mrUC). Non-limiting examples of standard treatmentinclude glucocorticosteriods, anti-TNF therapy, anti-a4-b7 therapy(vedolizumab), anti-IL12p40 therapy (ustekinumab), Thalidomide, andCytoxin.

The terms “treat,” “treating,” and “treatment” as used herein refers toalleviating or abrogating a disorder, disease, or condition; or one ormore of the symptoms associated with the disorder, disease, orcondition; or alleviating or eradicating a cause of the disorder,disease, or condition itself. Desirable effects of treatment caninclude, but are not limited to, preventing occurrence or recurrence ofdisease, alleviation of symptoms, diminishing any direct or indirectpathological consequences of the disease, preventing metastasis,decreasing the rate of disease progression, amelioration or palliationof the disease state and remission or improved prognosis.

The term “therapeutically effective amount” refers to the amount of acompound or therapy that, when administered, is sufficient to preventdevelopment of, or alleviate to some extent, one or more of the symptomsof a disorder, disease, or condition of the disease; or the amount of acompound that is sufficient to elicit biological or medical response ofa cell, tissue, system, animal, or human that is being sought by aresearcher, veterinarian, medical doctor, or clinician.

The term “pharmaceutically acceptable carrier,” “pharmaceuticallyacceptable excipient,” “physiologically acceptable carrier,” or“physiologically acceptable excipient” refers to apharmaceutically-acceptable material, composition, or vehicle, such as aliquid or solid filler, diluent, excipient, solvent, or encapsulatingmaterial. A component can be “pharmaceutically acceptable” in the senseof being compatible with the other ingredients of a pharmaceuticalformulation. It can also be suitable for use in contact with the tissueor organ of humans and animals without excessive toxicity, irritation,allergic response, immunogenicity, or other problems or complications,commensurate with a reasonable benefit/risk ratio. See, Remington: TheScience and Practice of Pharmacy, 21st Edition; Lippincott Williams &Wilkins: Philadelphia, Pa., 2005; Handbook of Pharmaceutical Excipients,5th Edition; Rowe et al., Eds., The Pharmaceutical Press and theAmerican Pharmaceutical Association: 2005; and Handbook ofPharmaceutical Additives, 3rd Edition; Ash and Ash Eds., GowerPublishing Company: 2007; Pharmaceutical Preformulation and Formulation,Gibson Ed., CRC Press LLC: Boca Raton, Fla., 2004).

The term “pharmaceutical composition” refers to a mixture of a compounddisclosed herein with other chemical components, such as diluents orcarriers. The pharmaceutical composition can facilitate administrationof the compound to an organism. Multiple techniques of administering acompound exist in the art including, but not limited to, oral,injection, aerosol, parenteral, and topical administration.

The term “inflammatory bowel disease” or “IBD” as used herein refers togastrointestinal disorders of the gastrointestinal tract. Non-limitingexamples of IBD include, Crohn's disease (CD), ulcerative colitis (UC),indeterminate colitis (IC), microscopic colitis, diversion colitis,Behcet's disease, and other inconclusive forms of IBD. In someinstances, IBD comprises fibrosis, fibrostenosis, structuring and/orpenetrating disease, obstructive disease, or a disease that isrefractory (e.g., mrUC, refractory CD), perianal CD, or othercomplicated forms of IBD.

Non-limiting examples of “sample” include any material from whichnucleic acids and/or proteins can be obtained. As non-limiting examples,this includes whole blood, peripheral blood, plasma, serum, saliva,mucus, urine, semen, lymph, fecal extract, cheek swab, cells or otherbodily fluid or tissue, including but not limited to tissue obtainedthrough surgical biopsy or surgical resection. In various embodiments,the sample comprises tissue from the large and/or small intestine. Invarious embodiments, the large intestine sample comprises the cecum,colon (the ascending colon, the transverse colon, the descending colon,and the sigmoid colon), rectum and/or the anal canal. In someembodiments, the small intestine sample comprises the duodenum, jejunum,and/or the ileum. Alternatively, a sample can be obtained throughprimary patient derived cell lines, or archived patient samples in theform of preserved samples, or fresh frozen samples.

The term “biomarker” comprises a measurable substance in a subject whosepresence, level, or activity, is indicative of a phenomenon (e.g.,phenotypic expression or activity; disease, condition, subclinicalphenotype of a disease or condition, infection; or environmentalstimuli). In some embodiments, a biomarker comprises a gene, geneexpression product (e.g., RNA or protein), or a cell-type (e.g., immunecell).

The term “serological marker,” as used herein refers to a type ofbiomarker representing an antigenic response in a subject that may bedetected in the serum of the subject. In some embodiments, a serologicalcomprises an antibody against various fungal antigens. Non-limitingexamples of a serological marker comprise anti-Saccharomyces cerevisiaeantibody (ASCA), an anti-neutrophil cytoplasmic antibody (ANCA), E. coliouter membrane porin protein C (OmpC), anti-Malassezia restrictaantibody, anti-Malassezia pachydermatis antibody, anti-Malassezia furfurantibody, anti-Malassezia globasa antibody, anti-Cladosporium albicansantibody, anti-laminaribiose antibody (ALCA), anti-chitobioside antibody(ACCA), anti-laminarin antibody, anti-chitin antibody, pANCA antibody,anit-I2 antibody, and anti-Cbir1 flagellin antibody.

The term “microbiome” and its variation used herein describe thepopulations and interactions of the bacteria, fungi, protists, and virusthat align the gastrointestinal tract of a subject. A subject afflictedwith IBD may possess presence, absence, excess, diminished, or acombination thereof of a microbiome s compared to a healthy subject.

The terms “non-response,” or “loss-of-response,” as used herein, referto phenomena in which a subject or a patient does not respond to theinduction of a standard treatment (e.g., anti-TNF therapy), orexperiences a loss of response to the standard treatment after asuccessful induction of the therapy. The induction of the standardtreatment may include 1, 2, 3, 4, or 5, doses of the therapy. A“successful induction” of the therapy may be an initial therapeuticresponse or benefit provided by the therapy. The loss of response may becharacterized by a reappearance of symptoms consistent with a flareafter a successful induction of the therapy.

The section headings used herein are for organizational purposes onlyand are not to be construed as limiting the subject matter described.

EXAMPLES

The following examples are included for illustrative purposes only andare not intended to limit the scope of the invention.

Example 1: Overview of the Identification of Genotypes

Tumor Necrosis Factor (Ligand) Superfamily, Member 15 (TNFSF15) has beendetermined to be significantly associated with inflammatory boweldisease (IBD), including Crohn's disease (CD), by Genome WideAssociation Studies (GWAS) (e.g., cases versus controls). In addition,increased levels of TL1A (e.g., RNA and protein) are associated withIBD, including CD. Therefore, therapeutic strategies targeting TNFSF15(TL1A) expression or activity offer a promising approach for thetreatment of IBD. Disclosed herein is the identification ofpolymorphisms that are associated with, and therefore predictive of, anincrease in TNFSF15 (TL1A) expression in patients with IBD, includingCD, using a machine learning approach.

A polygenic risk score (PRS) adapted to identify individuals at risk forhaving increased TNFSF15 (TL1A) was applied to a cohort of CD patientsrecruited atthe Cedars-Sinai Medical Center. A machine learningalgorithm (e.g., XGBoost) was used to identify combinations ofpolymorphisms associated with increased TNFSF15 (TL1A) expression oractivity. The resulting 41 polymorphisms, and a possible combinations ofpolymorphisms, have optimal prediction precision across multipleiterations of training the machine learning algorithm, which was able toanalyze large combinations of polymorphism interactions (e.g., includingnon-linear interactions) in an efficient manner, which traditional GWASmethodologies cannot achieve. The resulting polymorphisms are useful forselecting a subject, who may or may not be diagnosed with IBD, who mayexhibit a therapeutic response to an TNFSF15 (TL1A)-targetingtherapeutic agent (e.g., neutralizing anti-TL1A antibody).

Example 2: Calculation of TNFSF15 PRS

A polygenic risk score (PRS) based on polymorphisms within multiplegenes of interest (e.g., involved in the TL1A-mediated inflammatorypathways) and their associated weights in each respective referencepopulation was calculated. The PRS is referred to herein as the “TNFSF15PRS.” The polymorphisms were selected from multiple GWAS based on adefined distances from the transcription start and stop sites for thegene(s) of interest (e.g., 250 kilobases upstream and downstream). EachGWAS was to define the individual weights for contribution of apolymorphism to the total score. The GWAS used include, but are notlimited to, Jostins et al., 2012. Nature. 491:119-124, Liu et al., 2015.Nat Genet. 47:979-986, Ellinghaus et al., 2016. Nat Genet. 48:510-518,Huang et al., 2017. Nat Genet. 49:256-261, and de Lange et al., 2017.Nat Genet. 48:256-261.

To confirm the relevance of inclusion of a polymorphism within theTNFSF15 PRS, the polymorphisms were cross-checked by (i) evidence ofcis-QTL, where the SNP is directly associated with target geneexpression in tissues and (ii) sensitivity analysis, where selectedpolymorphisms are removed from the TNFSF15 PRS and a regression analysisis run against disease susceptibility and subclinical phenotypes, thushighlighting relevant polymorphisms to disease risk. In some cases, thepolymorphisms were subjected to sensitivity analysis, and in othercases, they were not. For example, in some cases, only thosepolymorphisms with questionable association to the pathway TNFSF15 PRS(e.g., no eQTL or multiple genes within the loci) are subjected tosensitivity analysis.

Patients with Crohn's disease (CD) were recruited. The diagnosis of eachpatient was based on standard endoscopic, histologic, and radiographicfeatures. Blood samples were collected from patients at the time ofenrollment. Genotyping was performed using Immunochip (ICHIP) permanufacturer's protocol on all samples collected.

A TNFSF15 PRS was calculated for Caucasian patients within aCedars-Sinai CD cohort from Example 1, based on the defined set ofpolymorphisms selected in this Example 2, which are provided in Table 4.An exemplary calculation of TNFSF15 PRS is outlined in Li et al., 2018.Inflamm Bowel Dis. 12; 24(11):2413-2422. The TNFSF15 PRS is calculatedas the weighted sum of the number of risk alleles carried by eachpatient (in the Cedars-Sinai CD cohort) (0, 1, or 2) at each loci forthe genes described in this Example 2, divided by a total number ofgenetic variants used in the model. The same calculations were performedfor each individual belonging to a reference group, thereby generating arange of raw scores (observed range). The resulting TNFSF15 PRS isgenerated by comparing the score of each patient with the observed rangeobserved in the reference group.

TABLE 4 TNFSF15 Polygenic Risk Score (PRS) Polymorphisms Minor Seq MinorAllele Major ID rsID Illumina_id Allele Frequency Allele Chromosome GeneNo. rs11221332 imm_11_127886184 A 0.232475 G chr11 ETS1 41 rs7134599imm_12_66786342 A 0.381954 G chr12 IFNG 42 rs6062496 imm_20_61799543 G0.406514 A chr20 TNFRSF6B 43 rs4246905 imm_9_116593070 A 0.270925 Gchr9  TNFSF15 8 rs7468800 imm_9_116631826 A 0.124622 C chr9  TNFSF15; 44TNFSF8 rs1569328 rs1569328 A 0.14869 G chr14 U2; FOS 45 rs2284553rs2284553 A 0.386244 G chr21 IFNGR2 46 rs6062504 rs6062504 A 0.27128 Gchr20 ZGPAT 47 rs7556897 rs7556897 G 0.334936 A chr2  SLC19A3; 48 CCL20

Example 3: XGBoost Machine Learning Algorithm Trained on BinaryClassifiers Based on TNFSF15 Polygenic Risk Score

A binary classifier to be used in the XGloost machine learning platformfor CD samples was created based on the distribution of the TNFSF15 PRSscores (calculated in Example 2) across the CD cohort. In this example,patient samples from the CD cohort were classified as 0 if their TNFSF15PRS was ≤25th percentile of the TNFSF15 PRS CD distribution. Patientsamples were classified as 1 if their TNFSF15 PRS was ≥75th percentileof the TNFSF15 PRS CD distribution.

Once the initial classifier of TNFSF15SNPs was established, the XGloostalgorithm was optimized for the polymorphisms and implemented togenerate an initial list of candidate polymorphisms. XGfoost is rootedin the gradient boosted decision trees, which in contrast to lasso andridge regression methods, incorporates complex non-linear featureinteractions into prediction models in anon-additive form. Exemplaryoptimization and implementation procedures are provided in Behravan etal. Sci Rep. 2018; 8:13149. A total of ten iterations of 5-fold crossvalidation were used to obtain an initial list of candidatepolymorphisms. These polymorphisms were further filtered/optimized usingan adaptive iterative search procedure as outlined in Behravan et al. aswell as support vector machines (SVM) resulting in a final list of SNPs,which had high prediction precision (>90%) for the TNFSF15 PRS binaryclassifier.

Example 4: XGBoost Machine Learning Algorithm Trained on BinaryClassifiers Based on TNFSF15 Protein Expression

Patients with Crohn's disease (CD) were recruited. The diagnosis of eachpatient was based on standard endoscopic, histologic, and radiographicfeatures. Blood samples were collected from the patients. All patientswere genotyped either by Illumina ImmunoArray or polymerase chainreaction (PCR) under standard hybridization conditions. Peripheral bloodmononuclear cells (PBMCs) were isolated from the blood samples. ThePMBCs were stimulated in vitro with immune complex. Supernatants werecollected from unstimulated samples and from stimulated samples at 6,18, 24, and 72 hours. Soluble TL1A protein in the supernatants wasquantified using a plate-based ELISA using and monoclonal antibodies atall time points.

Binary classifiers to be used in the XGBoost machine learning platformfor the samples were derived using TL1A protein expression levels at 6hours. The classifier at 6 hours reflects absolute levels of TL1Aprotein expression at that time point. Additional binary classifierswere derived using the results of clustering of samples (k=2 and k=3groups) based on TNFSF15 protein expression across 6, 18, 24, and72-hour time points. The classifiers at the combination of time points(e.g., 6, 18, 24, and 72) reflect a rate of production of TL1A betweentime points. The clustering was performed using the TMixClustBioconductor package as described in Golumbeanu et al. (“Clustering timeseries gene expression data with TMixClust 2018). A set of predictiveSNPs was obtained from each of the three XGBoost analyses of the threeclassifiers. The polymorphisms identified here were compared to the listof polymorphisms generated in Example 3 to identify only thosepolymorphisms that overlap between the two analyses.

Determination of overlaps of SNPs was performed on the gene annotation(refGene annotation) of the generated SNPs and not on the actual ICHIPor dbSNP reference sequence identification numbers. Only polymorphismswith minor allele frequencies (MAF)>0.1 and the beta coefficients (fromsupport vector machine (SVM) runs) with absolute values >0.1 were kept.This resulted in 129 polymorphisms remaining for further analysis. The 9polymorphisms used in the TNFF15 PRS (Table 4) were also added to thislist of SNPs, resulting in a total of 138 SNPs.

Example 5: Implementation of Market Basket Analysis to DetermineNon-Linear Polymorphism Combination Rules Associated with CD

In order to further filter out SNPs not strongly associated withclinical phenotypes, a market basket analysis approach was used todetermine combination rules for the polymorphisms associated withCrohn's Disease (CD) clinical phenotypes. An exemplary market basketanalysis is described in Breuer et al. Int J Bipolar Disord. 2018;6:24). The initial dataset on CD localization and CD characterizationwas obtained from 1,803 CD cohorts from Cedars-Sinai Medical Center. TheRUDI (Rule Discoverer) program (dominant minor model), also described inBreuer et al., was run on the 1,803 CD cohorts using the genotypes ofthe previously generated 138 SNPs (Example 4). The analysis resulted in57 rules with significant associations with clinical phenotypes forCrohn's Disease. The clinical phenotypes used in the analysis were CDlocation (ileum, colon, and ilealcolon), CD characterization(non-structuring/non-penetrating, structuring, structuring and internalpenetrating, and isolated internal penetrating), and presence ofperianal disease. The 57 association rules consisted of only 89 out ofthe 138 input polymorphisms from Example 4. Therefore, only these 89polymorphisms were considered for further evaluation.

Finally, support vector machines (SVM) analysis based on the 3 binaryclassifiers described in Example 3 and Example 4 were re-applied to thislist of 89 polymorphisms. Only XGBoost models (and their correspondingpolymorphisms) with a prediction precision >0.70 were maintained. Andfurther, only the polymorphisms from these models with an SVMcoefficient ≥0.25 or an SVM coefficient ≤−0.25 were kept. Applying thesefilters, a total of 41 polymorphisms were generated when analyzing all 3classifiers. These polymorphisms and reference alleles are provided inTable 1. The nucleic acid sequences comprising the polymorphisms areprovided in SEQ ID NOS: 1-41, or 57-59, and the position of thepolymorphism within the nucleic acid sequence is indicated with anon-nucleobase letter (e.g., V, R, S, and the like). The sequencesprovided are from build 151.

The polymorphisms identified in the analysis provided in the Examplesabove may be used to predict a positive therapeutic response in asubject or a patient to an inhibitor of TL1A activity or expression(e.g., anti-TL1A antibody), either alone, or in combinations (e.g., 2,3, 4, 5, 6, 7, and so forth). The polymorphisms described herein may beused in a diagnostic or prognostic test to identify a subject suitablefor treatment with an inhibitor of TL1A activity or expression to treata disease or condition described herein in the subject. In some cases,the diagnostic is a companion diagnostic test, such as for example, aTL1A companion diagnostic test (“TL1A CDx”).

In a non-limiting example, any combination of three polymorphisms, eachselected from Table 1, may be used to predict a positive therapeuticresponse to an inhibitor of TL1A activity or expression. Exemplarythree-polymorphism combinations include: imm_9_116608587,imm_11_127948309, and rs1892231; imm_9_116608587, imm_11_127948309, andrs9806914; imm_9_116608587, imm_11_127948309, and imm_21_44478192;imm_9_116608587, imm_11_127948309, and imm_21_44479552 imm_9_116608587,rs1892231, and rs9806914; imm_9_116608587, rs1892231, andimm_21_44478192; imm_9_116608587, rs1892231, and imm_21_44479552;imm_9_116608587, rs9806914, and imm_21_44478192; imm_9_116608587,rs9806914, and imm_21_44479552; imm_9_116608587, imm_21_44478192, andimm_21_44479552; imm_11_127948309, rs1892231, and rs9806914;imm_11_127948309, rs1892231, and imm_21_44478192; imm_11_127948309,rs1892231, and imm_21_44479552; imm_11_127948309, rs9806914, andimm_21_44478192; imm_11_127948309, rs9806914, and imm_21_44479552;imm_11_127948309, imm_21_44478192, and imm_21_44479552; rs1892231,rs9806914, and imm_21_44478192; rs1892231, rs9806914, andimm_21_44479552; rs1892231, imm_21_44478192, and imm_21_44479552; andrs9806914, imm_21_44478192, and imm_21_44479552.

Table 5 provides a table with the position of each polymorphism providedin Table 1 within the human genome according to GRCh38.p13 PrimaryAssembly. The nucleic acid sequence flanking each polymorphism isidentified with the relevant SEQ ID NO.

TABLE 5 GRCh38.p13 Primary Assembly Positions of Polymorphisms SEQ IDdbSNP NO: SNP_SEQ_GRCh38.p13 Primary Assembly rs1189773260 >NC_000002.12:43313747-43314246 Homo sapiens chromosome 2 SEQ =[G/A] >NC_000002.12:433 14248-43314747 Homo sapiens chromosome 2rs6740739 61 >NC_000002.12:43628004-43628503 Homo sapiens chromosome 2SEQ = [G/A] >NC_000002.12:43628505-43629004 Homo sapiens chromosome 2rs17796285 62 >NC_000008.11:11266446-11266945 s Homo sapiens chromosome8 SEQ = [G/A] >NC_000008.11:11266947-11267446 Homo sapiens chromosome 8rs7935393 63 >NC_000011.10:128572704-128573203s Homo sapiens chromosome11 SEQ = [A/C] >NC_000011.10:128573205-128573704 Homo sapiens chromosome11 rs12934476 64 >NC_000016.10:11237152-11237651 Homo sapiens chromosome16 SEQ = [G/A] >NC_000016.10:11237653-11238152 Homo sapiens chromosome16 rs12457255 65 >NC_000018.10:12759477-12759976 Homo sapiens chromosome18 SEQ = [C/A] >NC_000018.10:12759978-12760477 Homo sapiens chromosome18 rs2070557 66 >NC_000021.9:44234741-44235240 Homo sapiens chromosome21 SEQ = [A/T] >NC_000021.9:44235242-44235741 Homo sapiens chromosome 21rs4246905 67 >NC_000009.12:114790469-114790968 Homo sapiens chromosome 9SEQ = [T/A/ >NC_000009.12:114790970-114791469 Homo sapiens chromosome 9rs10974900 68 >NC_000009.12:4987458-4987957 Homo sapiens chromosome 9SEQ = [C/T] >NC_000009.12:4987959-4988458 s Homo sapiens chromosome 9rs12434976 69 >NC_000014.9:98185370- 98185869 Homo sapiens chromosome 14SEQ = [A/C] >NC_000014.9:98185871- 98186370 Homo sapiens chromosome 14rs16901748 70 >NC_000005.10:11561609-11562108 Homo sapiens chromosome 5SEQ = [G/T] >NC_000005.10:11562110-11562609 Homo sapiens chromosome 5rs2815844 71 >NC_000001.11:241083704-241084203 Homo sapiens chromosome 1SEQ = [C/T] >NC_000001.11:241084205-241084704 Homo sapiens chromosome 1rs889702 72 >NC_000016.10:6088639-608913 8 Homo sapiens chromosome 16SEQ = [G/A] >NC_000016.10:6089140-608963 9 Homo sapiens chromosome 16rs2409750 73 >NC_000008.11:11229685-11230184 Homo sapiens chromosome 8SEQ = [A/C] >NC_000008.11:11230186-11230685 Homo sapiens chromosome 8rs1541020 74 >NC_000010.11:6122567-6123066 Homo sapiens chromosome 10SEQ = [C/T] >NC_000010.11:6123068-6123567 Homo sapiens chromosome 10rs4942248 75 >NC_000013.11:43832169-43832668 Homo sapiens chromosome 13SEQ = [T/A] >NC_000013.11:43832670-43833169 Homo sapiens chromosome 13rs12934476 76 >NC_000016.10:11237152-11237651 Homo sapiens chromosome 16SEQ = [G/A] >NC_000016.10:11237653-11238152 Homo sapiens chromosome 16rs12457255 77 >NC_000018.10:12759477-12759976 Homo sapiens chromosome 18SEQ = [C/A] >NC_000018.10:12759978-12760477 Homo sapiens chromosome 18rs2297437 78 >NC_000020.11:63673421-63673920 Homo sapiens chromosome 20SEQ = [G/A] >NC_000020.11:63673 922-63674421 Homo sapiens chromosome 20rs41309367 79 >NC_000020.11:63677701-63678200 Homo sapiens chromosome 20SEQ = [C/T] >NC_000020.11:63678202-63678701 Homo sapiens chromosome 20rs10733509 80 >NC_000009.12:4307550-4308049 Homo sapiens chromosome 9SEQ = [G/A] >NC_000009.12:4308051-4308550 Homo sapiens chromosome 9rs10750376 81 >NC_000011.10:127867534-127868033 Homo sapiens chromosome11 SEQ = [C/T] >NC_000011.10:127868035-127868534 Homo sapiens chromosome11 rs10932456 82 >NC_000002.12:212988031-212988530 Homo sapienschromosome 2 SEQ = [G/A] >NC_000002.12:212988532-212989031 Homo sapienschromosome 2 rs1326860 83 >NC_000001.11:193834579-193835078 Homo sapienschromosome 1 SEQ = [G/A] >NC_000001.11:193835080-193835579 Homo sapienschromosome 1 rs1528663 84 >NC_000011.10:13945175-13945674 Homo sapienschromosome 11 SEQ = [G/A] >NC_000011.10:13945676-13946175 Homo sapienschromosome 11 rs1892231 85 >NC_000014.9:98267730-98268229 s Homo sapienschromosome 14 SEQ = [A/C] >NC_000014.9:98268231-98268730 Homo sapienschromosome 14 rs951279 86 >NC_000001.11:208593050-208593549 Homo sapienschromosome 1 SEQ = [G/A] >NC_000001.11:208593551-208594050 Homo sapienschromosome 1 rs9806914 87 >NC_000016.10:6097144-6097643 Homo sapienschromosome 16 SEQ = [A/C] >NC_000016.10:6097645-6098144 Homo sapienschromosome 16 rs7935393 88 >NC_000011.10:128572704-128573203 Homosapiens chromosome 11 SEQ = [A/C] >NC_000011.10:128573205-128573704 Homosapiens chromosome 11 rs1690492 89 >NC_000016.10:11224459-11224958 Homosapiens chromosome 16 SEQ = [G/C] >NC_000016.10:11224960-11225459 Homosapiens chromosome 16 rs420726 90 >NC_000021.9:44239062-44239561 Homosapiens chromosome 21 SEQ = [T/C] >NC_000021.9:44239563-44240062 Homosapiens chromosome 21 rs7759385 91 >NC_000006.12:106140395-106140894Homo sapiens chromosome 6 SEQ = [T/A] >NC_000006.12:106140896-106141395Homo sapiens chromosome 6 rs10974900 92 >NC_000009.12:4987458-4987957Homo sapiens chromosome 9 SEQ = [C/T] >NC_000009.12:4987959-4988458 Homosapiens chromosome 9 rs1326860 93 >NC_000001.11:193834579-193835078 Homosapiens chromosome 1 SEQ = [G/A] >NC_000001.11:193835080-193835579 Homosapiens chromosome 1 rs2548147 94 >NC_000005.10:40151459-40151958 Homosapiens chromosome 5 SEQ = [G/C] >NC_000005.10:40151960-40152459 Homosapiens chromosome 5 rs2815844 95 >NC_000001.11:241083704-241084203 Homosapiens chromosome 1 SEQ = [C/T] >NC_000001.11:241084205-241084704 Homosapiens chromosome 1 rs889702 96 >NC_000016.10:6088639-6089138 Homosapiens chromosome 16 SEQ = [G/A] >NC_000016.10:6089140-6089639 Homosapiens chromosome 16 rs9806914 97 >NC_000016.10:6097144-6 97643 Homosapiens chromosome 16 SEQ = [A/C] >NC_000016.10:6097645-6098144 Homosapiens chromosome 16 rs6478109 98 >NC_000009.12:114805986-114806485Homo sapiens chromosome 9 SEQ = [G/A] >NC_000009.12:114806487-114806986Homo sapiens chromosome 9 rs7278257 99 >NC_000021.9:44233381-44233880Homo sapiens chromosome 21 SEQ = [G/C] >NC_000021.9:44233882-44234381Homo sapiens chromosome 21 rs11221332100 >NC_000011.10:128510579-12851078 Homo sapiens chromosome 11 SEQ =[C/A/ >NC_000011.10:128511080-128511579 Homo sapiens chromosome 11rs56124762 101 >NC_000021.9:44238091-44238590 Homo sapiens chromosome 21SEQ = [G/A] >NC_000021.9:44238592-44239091 Homo sapiens chromosome 21rs2070558 102 >NC_000021.9:44235275-44235774 Homo sapiens chromosome 21SEQ = [G/A] >NC_000021.9:44235776-44236275 Homo sapiens chromosome 21rs2070561 103 >NC_000021.9:44237587-44238086 Homo sapiens chromosome 21SEQ = [T/C] >NC_000021.9:44238088-44238587 Homo sapiens chromosome 21rs7134599 104 >NC_000012.12:68105795-68106294 Homo sapiens chromosome 12SEQ = [G/A] >NC_000012.12:68106296-68106795 Homo sapiens chromosome 12rs6062496 105 >NC_000020.11:63697246-63697745 Homo sapiens chromosome 20SEQ = [G/A] >NC_000020.11:63697747-63698246 Homo sapiens chromosome 20rs7468800 106 >NC_000009.12:114829225-114829724 Homo sapiens chromosome9 SEQ = [C/A] >NC_000009.12:114829726-114830225 Homo sapiens chromosome9 rs1569328 107 >NC_000014.9:75274548-75275047 chromosome 14 SEQ =[C/T] >NC_000014.9:75275049-75275548 Homo sapiens chromosome 14rs2284553 108 >NC_000021.9:33403889-33404388 Homo sapiens chromosome 21SEQ = [G/A] >NC_000021.9:33404390-33404889 Homo sapiens chromosome 21rs6062504 364141 >NC_000020.11:63717055-63717554 Homo sapiens chromosome20 SEQ = [A/G/ >NC_000020.11:63717556-63718055 Homo sapiens chromosome20 rs7556897 364142 >NC_000002.12:227794896-227795395 Homo sapienschromosome 2 SEQ = [C/G/ >NC_000002.12:227795397-227795896 Homo sapienschromosome 2

Example 6. Validation of 3-SNP Models for TL1A Companion Diagnostic

The machine learning workflow identified several SNP model combinationsfor the development of the TL1A companion diagnostic (TL1A CDx).Previous analyses had identified 3-SNP combination models composed ofvariants associated with TNFSF15 (rs6478109), ICOSLG(rs7278257,rs2070557), ETS (rs7935393), and RBFOXJ (rs9806914) genes as well asvariant rs1892231. These SNP models were identified via a Cedars SinaiCrohn's Disease cohort. In order to validate the findings, an externalcohort of Crohn's Disease patients was identified and genotyped.Genotype and TL1A protein expression were obtained from the non-Cedarscohort in order to validate the 3-SNP models. A total of 712 Crohn'sDisease individuals were genotyped while a 114 subset of the 712 sampleswere used to obtain TL1A protein expression via PBMC assays.

Genotyping and Imputation of Cohort

The initial data mining analyses was performed on a Cedars Sinai cohortusing genotypes from the Illumina's ICHIP (Immunochip) platform. Thevalidation cohort was genotyped using Illumina's GSA platform (24v2.0),which has substantial improvements over the Immunochip platform. Most ofthe SNPs identified in the models were not present on the GSA platform.Therefore, imputation of the GSA genotype data was initiated in order toobtain a larger panel of genotyped SNPs so the SNP models could bevalidated. Genotype imputation refers to the prediction of genotypesthat are not directly assayed on a given platform. Differentmethodologies and significant improvements in algorithms have beendeveloped for implementing genotype imputation. The quality of thegenotype imputation was validated by selecting a random sample of 120patients from our validation cohort to be genotyped for a small set ofimputed SNPs. The overall agreement between imputed genotype and assaygenotypes were evaluated using Cohen's Kappa statistic.

Validation cohort genotyped results were downloaded from Illumina andtransformed into PED format (through Illumina's Genome Studio Workbench)so that they could be further processed using the PLINK software (v1.9).The genotyped data went through a process of QC looking at factors suchas heterozygosity, SNP missingness, MAF distributions, and relatednessof samples in order to prepare the genotype data for ancestrydetermination. Once genotyped data was QCed, the admixture and ancestryPCA plots were used to determine which samples were of European (EUR)ancestry to move forward with imputation. In order to performimputation, ancestry needs to be taken into account, since genotypereference panels based on ancestry are used by imputation algorithms.For our imputation, the European Reference Panel: hrc.r1.1 for thereference panel was selected. All qc'd EUR ancestry genotyped sampleswere submitted to the Michigan Imputation Server for genotypeimputation. The resulting imputed genotypes were downloaded and furtherprocessed for model validation.

In order to move forward with analyzing the imputed genotypes for the3-SNP model validation, a random selection of 120 samples from theinitial 470 samples were sent to Illumina for genotyping in order tocompare the imputed genotype with the actual laboratory genotyperesults. The imputed genotypes were evaluated by looking at the level ofagreement for the following SNPs: rs6478109, rs2070557, rs1892231,rs7935393.

The SNP rs6478109 was already on the GSA platform and this was used as a“control” to determine that the assay was in fact working appropriately.The levels of agreement (based on Cohen's Kappa) were high (based on thetable below) and therefore it was decided to move forward with using theimputed genotype data for further analysis.

TABLE 7 Levels of Agreement Based On Cohen's Kappa Cohen's SNP Rsq Kappars6478109 0.998 1.00 rs2070557 0 978 0.98 rs1892231 0.989 1.00 rs79353930.980 1.00

Evaluation and Validation of 3-SNP Models

Next, the initial 3-SNP models were evaluated using the validationcohort. Similar to the analysis of the Cedars cohort TL1A proteinexpression data, the TL1A Expression (based on PBMC assay) from thevalidation cohort was clustered using the TL1A measurements at the 0, 3,6, 24, and 72 hour time points. The clustering identified 3 clusterwithin the dataset, which are provided in FIG. 5A-5C. FIG. 5A showscluster 1, FIG. 5B shows cluster 2, and FIG. 5C shows cluster 3.

The 3 clusters were collapsed into 2 clusters (high expression clusters)and (low expression clusters), which are shown in FIG. 6. The clustersabove were collapsed down to two clusters because there was substantialoverlap between cluster 3 (FIG. 5C) above and cluster 1 (FIG. 6, left).The same level of overlap was seen for clusters 1 (FIG. 5A) and 2 (FIG.5B) (based on the 3 clusters) and cluster 2 (FIG. 6, right).

The imputed genotype data were integrated from the validation cohortwith the TL1A protein expression data in order to determine which modelsvalidated in the external validation cohort. This was done by looking atresults of the TL1A CDx 3-SNP model. The 3-SNP models were evaluated inthe context of the validation cohort and the TL1A expression clusters.“Positive” genotype hits were determined based on the association of aparticular genotype and its ability to associate with the higherexpressing TL1A cluster. Without being bound by any particular theory,high TL1A clusters (e.g., high expression of TL1A in CD patients,relative to baseline expression of TL1A in normal individuals) directlycorrelates with positive therapeutic responsiveness to an inhibitor ofTL1A activity or expression; whereas low TL1A clusters (e.g., low TL1Aexpression in CD patients, relative to baseline expression of TL1A innormal individuals) directly correlates to non-responsiveness to aninhibitor of TL1A activity or expression.

Calculations of Positive Predictive Value (PPV) and Specificity werecalculated for the 3-SNP models. Each model consists of 3 unique SNPsbased off of the identified SNPs in our training cohort analysis (TNFSF5(rs6478109), ICOSLG(rs7278257, rs2070557), ETS (rs7935393), and RBFOX1(rs9806914) genes as well as variant rs1892231). The PPV and Specificityfor Models A-C are provided in Table 8. As shown in Table 8, Model A maybe used to predict a positive therapeutic response to a treatment withan inhibitor of TL1A activity or expression with a PPV of at least orabout 0.797 and a specificity of at least or about 0816 (whenconsidering both training and validation cohorts combined). Model A wasfurther explored due to its better performance compared to Models B andC (when considering both training and validation cohorts combined).

TABLE 8 Exemplary 3-SNP Models A-C Training Validation Cohort CohortCombined CD Model PPV SPEC PPV SPEC PPV SPEC FREQ A 0.902 0.867 0.6430.783 0.797 0.816 38.7 B 0.806 0.767 0.682 0.848 0.759 0.816 26.3 C0.838 0.800 0.576 0.696 0.714 0.737 36.7

Other previously identified 3-SNP models were further evaluated due thefact that only Model A showed strong concordance of positive hitgenotypes across the training and validation cohorts. These additionalSNP models (Models D-K) consisted of 3-SNP combinations of the followingSNPs: rs6478109, rs7935393, rs9806914, rs16901748, rs2070557, rs7278257,rs2297437, rs1892231, as shown in Table 9.

TABLE 9 3-SNP Models D-K Cohort Cohort 1 2 Combined CD Model PPV SPECPPV SPEC PPV SPEC FREQ D 0.815 0.833 0.750 0.848 0.782 0.842 18.6 E0.848 0.833 0.606 0.717 0.727 0.763 31.2 F 0.909 0.933 0.667 0.870 0.8000.895 18.3 G 0.917 0.933 0.609 0.804 0.766 0.855 22.6 H 0.923 0.9670.727 0.935 0.833 0.947 12.9 I 0.941 0.967 0.733 0.913 0.844 0.934 17.2J 0.923 0.967 0.727 0.935 0.833 0.947 12.9 K 0.844 0.833 0.731 0.8480.793 0.842 23.9

As before, the PPV and Specificity for each model was evaluated in thecontext of positive and negative hits and their association with highand lower TL1A clusters. After evaluating the models across bothtraining and validation cohorts, an additional model (Model K) wasevaluated, which contained SNP, rs16901748 (CTNND2), which had not beenutilized in our previous models (based on the initial training cohort).

ICOSLG Proxy SNP Selection

One of ICOSLG SNPs (rs7278257) was determined to be challenging togenotype given the SNP location within the genome. Therefore, candidateproxy SNPs to rs7278257 were identified. The proxy SNPs were identifiedvia LDLink. A list of potential proxy SNPs for rs7278257 is shown belowin Table 10.

TABLE 10 Proxy SNPs Utilized in Validation RS_Number Coord Alleles MAFDistance Dprime R2 rs7278257 chr21: 45653764 (G/C) 0.2833 0 1 1rs56124762 chr21: 45658474 (A/G) 0.2763 4710 0.9849 0.9372 rs11558819chr21: 45656774 (C/T) 0.2873 3010 0.9705 0.9236 rs2070557 chr21:45655124 (A/T) 0.2972 1360 0.9651 0.8705 rs2070558 chr21: 45655658 (G/A)0.2952 1894 0.9602 0.87 rs2329718 chr21: 45656199 (T/C) 0.2952 24350.9602 0.87 rs2070559 chr21: 45657700 (C/G) 0.2982 3936 0.96 0.8573rs2070560 chr21: 45657848 (C/G) 0.2972 4084 0.9551 0.8526 rs2070561chr21: 45657970 (T/C) 0.2972 4206 0.9551 0.8526

Next, the SNPs provided in Table 10 were analyzed for relevantinflammatory bowel disease related clinical associations within theCedars R/Shiny database. From the SNPs above, the following SNPs hadrelevant clinical associations (examples include key phenotypes: CD vs.Ctrl,IBD vs. Ctrl,L1 B2a+B2b vs B1): rs2070561, rs56124762, rs2070558,rs11558819. CD v. Ctrl refers to cases of Crohn's disease versus casesof controls (individuals without Crohn's disease); IBD vs. Ctrl refersto cases of inflammatory bowel disease versus cases of controls(individuals without IBD); L1 refers to the ileum; B2a+B2b refers tostructuring and penetrating disease; B1 refers to non-structuring andnon-penetrating disease.

Example 7. Validation in Japanese Cohort

An external cohort of Crohn's Disease patients of Japanese ancestry isidentified and genotyped. Genotype and TL1A protein expression areobtained from second Japanese cohort in order to validate the 3-SNPmodels. A total of 800 Crohn's Disease individuals are genotyped while a100 subset of the 800 samples are used to obtain TL1A protein expressionvia PBMC assays.

The initial 3-SNP models are evaluated using the Japanese validationcohort. Similar to the analysis of the validation cohort in Example 6,the TL1A Expression (based on PBMC assay) from the validation cohort isclustered using the TL1A measurements at the 0, 3, 6, 24, and 72 hourtime points. The clustering identifies at least 2 clusters in thedataset: (i) high expression clusters and (ii) low expression clusters.

The imputed genotype data are integrated from the Japanese validationcohort with the TL1A protein expression data in order to determine whichmodels validated in the Japanese validation cohort. This is done bylooking at results of the TL1A CDx 3-SNP model. The 3-SNP models areevaluated in the context of the Japanese validation cohort and the TL1Aexpression clusters. “Positive” genotype hits are determined based onthe association of a particular genotype and its ability to associatewith the higher expressing TL1A cluster. Calculations of PPV andSpecificity are calculated for the 3-SNP models. Each model consists of3 unique SNPs based off of the identified SNPs in the training cohortanalysis (TNFSF15 (rs6478109), ICOSLG(rs7278257, rs2070557), ETS(rs7935393), and RBFOX1 (rs9806914) genes as well as variant rs1892231).The 3-SNP models shown in Table 8 and Table 9 are explored in thisvalidation. The PPV and SPEC values expected in the Japanese validationcohort for Models A-K are the same as those reported in Table 8 and 9.Without being bound by any particular theory, validation of the 3-SNPmodels for the TL1A CDx is expected across all ancestral populations.

Candidate proxy SNPs to any one of the SNPs provided in Table 8 or Table9 may be identified. The proxy SNPs are identified via LDLink using areference population of Japanese ancestry. The proxy SNPs are furtheranalyzed for relevant inflammatory bowel disease related clinicalassociations within the Cedars R/Shiny database in Japanese cohorts,such as for example, CD vs. Ctrl,IBD vs. Ctrl,L1 B2a+B2b vs B1).

Example 8: Phase I Clinical Trial

A phase 1 clinical trial is performed to evaluate the safety,tolerability, pharmacokinetics and pharmacodynamics of an anti-TL1Aantibody on subjects having Crohn's disease (CD).

Single ascending dose (SAD) arms: Subjects in each group (subjects aregrouped based on the presence of a genotype comprising at least one, andpreferably three, polymorphism(s) selected from Table 1 and subjectswithout the presence of the genotype) receive either a single dose ofthe antibody or a placebo. Exemplary doses are 1, 3, 10, 30, 100, 300,600 and 800 mg of antibody. Safety monitoring and PK assessments areperformed for a predetermined time. Based on evaluation of the PK data,and if the antibody is deemed to be well tolerated, dose escalationoccurs, either within the same groups or a further group of healthysubjects. Dose escalation continues until the maximum dose has beenattained unless predefined maximum exposure is reached or intolerableside effects become apparent.

Multiple ascending dose (MAD) arms: Subjects in each group (subjects aregrouped based on the same criteria as above) receive multiple doses ofthe antibody or a placebo. The dose levels and dosing intervals areselected as those that are predicted to be safe from the SAD data. Doselevels and dosing frequency are chosen to achieve therapeutic druglevels within the systemic circulation that are maintained at steadystate for several days to allow appropriate safety parameters to bemonitored. Samples are collected and analyzed to determination PKprofiles.

Inclusion Criteria: Healthy subjects of non-childbearing potentialbetween the ages of 18 and 55 years. Healthy is defined as no clinicallyrelevant abnormalities identified by a detailed medical history, fullphysical examination, including blood pressure and pulse ratemeasurement, 12 lead ECG and clinical laboratory tests. Female subjectsof non-childbearing potential must meet at least one of the followingcriteria: (1) achieved postmenopausal status, defined as: cessation ofregular menses for at least 12 consecutive months with no alternativepathological or physiological cause; and have a serum folliclestimulating hormone (FSH) level within the laboratory's reference rangefor postmenopausal females; (2) have undergone a documented hysterectomyand/or bilateral oophorectomy; (3) have medically confirmed ovarianfailure. All other female subjects (including females with tuballigations and females that do NOT have a documented hysterectomy,bilateral oophorectomy and/or ovarian failure) will be considered to beof childbearing potential. Body Mass Index (BMI) of 17.5 to 30.5 kg/m2;and a total body weight >50 kg (110 lbs). Evidence of a personallysigned and dated informed consent document indicating that the subject(or a legal representative) has been informed of all pertinent aspectsof the study.

Two groups of CD patients are selected: patients having the genotypedescribed herein, and patients without the genotype. For example, thegenotype may comprise rs6478109, rs56124762, and rs1892231; rs6478109,rs56124762, and rs16901748; rs6478109, rs1892231, and rs16901748;rs56124762, rs1892231, and rs16901748; rs6478109, rs2070558, andrs1892231; rs6478109, rs2070558, and rs16901748; rs6478109, rs1892231,and rs16901748; rs2070558, rs1892231, and rs16901748; rs6478109,rs2070561, and rs1892231; rs6478109, rs2070561, and rs16901748;rs6478109, rs1892231, and rs16901748; rs2070561, rs1892231, andrs16901748; rs6478109, rs7935393, and rs1892231; rs6478109, rs7935393,and rs9806914; rs6478109, rs7935393, and rs7278257; rs6478109,rs7935393, and rs2070557; rs6478109, rs1892231, and rs9806914;rs6478109, rs1892231, and rs7278257; rs6478109, rs1892231, andrs2070557; rs6478109, rs9806914, and rs7278257; rs6478109, rs9806914,and rs2070557; rs6478109, rs7278257, and rs2070557; rs7935393,rs1892231, and rs9806914; rs7935393, rs1892231, and rs7278257;rs7935393, rs1892231, and rs2070557; rs7935393, rs9806914, andrs7278257; rs7935393, rs9806914, and rs2070557; rs7935393, rs7278257,and rs2070557; rs1892231, rs9806914, and rs7278257; rs1892231,rs9806914, and rs2070557; rs1892231, rs7278257, and rs2070557; orrs9806914, rs7278257, and rs2070557.

Exclusion Criteria:

Evidence or history of clinically significant hematological, renal,endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic,psychiatric, neurologic, or allergic disease (including drug allergies,but excluding untreated, asymptomatic, seasonal allergies at time ofdosing). Subjects with a history of or current positive results for anyof the following serological tests: Hepatitis B surface antigen (HBsAg),Hepatitis B core antibody (HBcAb), anti-Hepatitis C antibody (HCV Ab) orhuman immunodeficiency virus (HIV). Subjects with a history of allergicor anaphylactic reaction to a therapeutic drug. Treatment with aninvestigational drug within 30 days (or as determined by the localrequirement, whichever is longer) or 5 half-lives or 180 days forbiologics preceding the first dose of study medication. Pregnantfemales; breastfeeding females; and females of childbearing potential.

Primary Outcome Measures:

Incidence of dose limiting or intolerability treatment related adverseevents (AEs) [Time Frame: 12 weeks]. Incidence, severity and causalrelationship of treatment emergent AEs (TEAEs) and withdrawals due totreatment emergent adverse events [Time Frame: 12 weeks]. Incidence andmagnitude of abnormal laboratory findings [Time Frame: 12 weeks].Abnormal and clinically relevant changes in vital signs, blood pressure(BP) and electrocardiogram (ECG) parameters [Time Frame: 12 weeks].

Secondary Outcome Measures:

Single Ascending Dose: Maximum Observed Plasma Concentration (Cmax)[Time Frame: 12 weeks]. Single Ascending Dose: Time to Reach MaximumObserved Plasma Concentration (Tmax) [Time Frame: 12 weeks]. SingleAscending Dose: Area under the plasma concentration-time profile fromtime zero to 14 days (AUC14 days) [Time Frame: 12 weeks]. SingleAscending Dose: Area under the plasma concentration-time profile fromtime zero extrapolated to infinite time (AUCinf) [Time Frame: 12 weeks].Single Ascending Dose: Area under the plasma concentration-time profilefrom time zero to the time of last quantifiable concentration (AUClast)[Time Frame: 12 weeks]. Single Ascending Dose: Dose normalized maximumplasma concentration (Cmax[dn]) [Time Frame: 12 weeks]. Single AscendingDose: Dose normalized area under the plasma concentration-time profilefrom time zero extrapolated to infinite time (AUCinf[dn]) [Time Frame:12 weeks]. Single Ascending Dose: Dose normalized area under the plasmaconcentration-time profile from time zero to the time of lastquantifiable concentration (AUClast[dn]) [Time Frame: 12 weeks]. SingleAscending Dose: Plasma Decay Half-Life (t½) [Time Frame: 12 weeks].Plasma decay half-life is the time measured for the plasma concentrationto decrease by one half. Single Ascending Dose: Mean residence time(MRT) [Time Frame: 12 weeks]. Single Ascending Dose: Volume ofDistribution at Steady State (Vss) [Time Frame: 6 weeks]. Volume ofdistribution is defined as the theoretical volume in which the totalamount of drug would need to be uniformly distributed to produce thedesired blood concentration of a drug. Steady state volume ofdistribution (Vss) is the apparent volume of distribution atsteady-state. Single Ascending Dose: Systemic Clearance (CL) [TimeFrame: 6]. CL is a quantitative measure of the rate at which a drugsubstance is removed from the body.

Multiple Ascending Dose First Dose: Maximum Observed PlasmaConcentration (Cmax) [Time Frame: 12 weeks]. Multiple Ascending DoseFirst Dose: Time to Reach Maximum Observed Plasma Concentration (Tmax)[Time Frame: 12 weeks]. Multiple Ascending Dose First Dose: Area underthe plasma concentration-time profile from time zero to time r, thedosing interval where i=2 weeks (AUCT) [Time Frame: 12 weeks]. MultipleAscending Dose First Dose: Dose normalized maximum plasma concentration(Cmax[dn]) [Time Frame: 12 weeks]. Multiple Ascending Dose First Dose:Dose normalized Area under the plasma concentration-time profile fromtime zero to time, the dosing interval where i=2 weeks (AUCT [dn]) [TimeFrame: 12 weeks]. Plasma Decay Half-Life (t½) [Time Frame: 12 weeks].Plasma decay half-life is the time measured for the plasma concentrationto decrease by one half. Multiple Ascending Dose First Dose: Meanresidence time (MRT) [Time Frame: 12 weeks]. Apparent Volume ofDistribution (Vz/F) [Time Frame: 12 weeks]. Volume of distribution isdefined as the theoretical volume in which the total amount of drugwould need to be uniformly distributed to produce the desired plasmaconcentration of a drug. Apparent volume of distribution after oral dose(Vz/F) is influenced by the fraction absorbed. Multiple Ascending DoseFirst Dose: Volume of Distribution at Steady State (Vss) [Time Frame: 12weeks]. Volume of distribution is defined as the theoretical volume inwhich the total amount of drug would need to be uniformly distributed toproduce the desired blood concentration of a drug. Steady state volumeof distribution (Vss) is the apparent volume of distribution atsteady-state. Multiple Ascending Dose First Dose: Apparent OralClearance (CL/F) [Time Frame: 12 weeks]. Clearance of a drug is ameasure of the rate at which a drug is metabolized or eliminated bynormal biological processes. Clearance obtained after oral dose(apparent oral clearance) is influenced by the fraction of the doseabsorbed. Clearance is estimated from population pharmacokinetic (PK)modeling. Drug clearance is a quantitative measure of the rate at whicha drug substance is removed from the blood. Multiple Ascending DoseFirst Dose: Systemic Clearance (CL) [Time Frame: 12 weeks]. CL is aquantitative measure of the rate at which a drug substance is removedfrom the body.

Multiple Ascending Dose Multiple Dose: Maximum Observed PlasmaConcentration (Cmax) [Time Frame: 12 weeks]. Multiple Ascending DoseMultiple Dose: Time to Reach Maximum Observed Plasma Concentration(Tmax) [Time Frame: 12 weeks]. Multiple Ascending Dose Multiple Dose:Area under the plasma concentration-time profile from time zero to timer, the dosing interval where τ=2 weeks (AUCT)[Time Frame: 12 weeks].Multiple Ascending Dose Multiple Dose: Dose normalized maximum plasmaconcentration (Cmax[dn]) [Time Frame: 12 weeks]. Multiple Ascending DoseMultiple Dose: Dose normalized Area under the plasma concentration-timeprofile from time zero to time r, the dosing interval where i=2 weeks(AUCτ [dn]) [Time Frame: 12 weeks]. Multiple Ascending Dose MultipleDose: Plasma Decay Half-Life (t½) [Time Frame: 12 weeks]. Plasma decayhalf-life is the time measured for the plasma concentration to decreaseby one half. Multiple Ascending Dose Multiple Dose: Apparent Volume ofDistribution (Vz/F) [Time Frame: 12 weeks]. Volume of distribution isdefined as the theoretical volume in which the total amount of drugwould need to be uniformly distributed to produce the desired plasmaconcentration of a drug. Apparent volume of distribution after oral dose(Vz/F) is influenced by the fraction absorbed. Multiple Ascending DoseMultiple Dose: Volume of Distribution at Steady State (Vss) [Time Frame:12 weeks]. Volume of distribution is defined as the theoretical volumein which the total amount of drug would need to be uniformly distributedto produce the desired blood concentration of a drug. Steady statevolume of distribution (Vss) is the apparent volume of distribution atsteady-state.

Multiple Ascending Dose Multiple Dose: Apparent Oral Clearance (CL/F)[Time Frame: 12 weeks]. Clearance of a drug is a measure of the rate atwhich a drug is metabolized or eliminated by normal biologicalprocesses. Clearance obtained after oral dose (apparent oral clearance)is influenced by the fraction of the dose absorbed. Clearance wasestimated from population pharmacokinetic (PK) modeling. Drug clearanceis a quantitative measure of the rate at which a drug substance isremoved from the blood. Multiple Ascending Dose Multiple Dose: SystemicClearance (CL) [Time Frame: 12 weeks]. CL is a quantitative measure ofthe rate at which a drug substance is removed from the body. MultipleAscending Dose Multiple Dose: Minimum Observed Plasma TroughConcentration (Cmin) [Time Frame: 12 weeks]. Multiple Ascending DoseMultiple Dose: Average concentration at steady state (Cav) [Time Frame:12 weeks]. Multiple Ascending Dose Multiple Dose: Observed accumulationratio (Rac) [Time Frame: 12 weeks]. Multiple Ascending Dose MultipleDose: Peakto trough fluctuation (PTF) [Time Frame: 12 weeks]. MultipleAscending Dose Additional Parameter: estimate of bioavailability (F) forsubcutaneous administration at the corresponding intravenous dose [TimeFrame: 12 weeks]. Immunogenicity for both Single Ascending Dose andMultiple Ascending Dose: Development of anti-drug antibodies (ADA) [TimeFrame: 12 weeks].

Example 9: Phase 1B Clinical Trial

A phase 1b open label clinical trial is performed to evaluate efficacyof an anti-TL1A antibody on subjects having CD.

Arms: 10 patients positive for genotypes comprising at least one, butpreferably three, polymorphism(s) provided in Table 1 are administeredthe antibody. 10 patients negative for the genotype are administered theantibody. Patients are monitored in real-time. Central ready ofendoscopy and biopsy is employed, with readers blinded to point of timeof treatment and endpoints.

For example, the genotypes may comprise rs6478109, rs56124762, andrs1892231; rs6478109, rs56124762, and rs16901748; rs6478109, rs1892231,and rs16901748; rs56124762, rs1892231, and rs16901748; rs6478109,rs2070558, and rs1892231; rs6478109, rs2070558, and rs16901748;rs6478109, rs1892231, and rs16901748; rs2070558, rs1892231, andrs16901748; rs6478109, rs2070561, and rs1892231; rs6478109, rs2070561,and rs16901748; rs6478109, rs1892231, and rs16901748; rs2070561,rs1892231, and rs16901748; rs6478109, rs7935393, and rs1892231;rs6478109, rs7935393, and rs9806914; rs6478109, rs7935393, andrs7278257; rs6478109, rs7935393, and rs2070557; rs6478109, rs1892231,and rs9806914; rs6478109, rs1892231, and rs7278257; rs6478109,rs1892231, and rs2070557; rs6478109, rs9806914, and rs7278257;rs6478109, rs9806914, and rs2070557; rs6478109, rs7278257, andrs2070557; rs7935393, rs1892231, and rs9806914; rs7935393, rs1892231,and rs7278257; rs7935393, rs1892231, and rs2070557; rs7935393,rs9806914, and rs7278257; rs7935393, rs9806914, and rs2070557;rs7935393, rs7278257, and rs2070557; rs1892231, rs9806914, andrs7278257; rs1892231, rs9806914, and rs2070557; rs1892231, rs7278257,and rs2070557; or rs9806914, rs7278257, and rs2070557.

Inclusion Criteria:

Two groups of patients are selected: subject with the genotype describedherein, and patients without the genotype.

Primary Outcome Measures:

Simple Endoscopic Score for Crohn's Disease (SESCD), Crohn's DiseaseActivity Index (CDAI), and Patient Reported Outcome (PRO). If riskeither positive group shows 50% reduction from baseline, a Phase 2aclinical trial is performed.

Inclusion Criteria:

PRO entry criteria: Abdominal pain score of 2 or more and/or stoolfrequency score of 4 or more. Primary outcome would be pain core of 0 or1 and stool frequency score of 3 or less with no worsening frombaseline. Endoscopy entry criteria: SESCD ileum only entry at score of 4and 6 if colon is involved. Primary endoscopic outcome is 40-50% deltaof mean SESCD.

Example 10: Phase 2A Clinical Trial

A phase 2a clinical trial is performed to evaluate the efficacy of ananti-TL1A antibody in patients with CD. Optionally, the patients arepositive for a genotype comprising at least one, but preferably three,polymorphism(s) provided in Table 1.

Arms:

40 patients per arm (antibody and placebo arms) are treated withantibody or placebo for 12 weeks. An interim analysis is performed after20 patients from each group are treated at the highest dose to look fora 40-50% delta between placebo and treated group in primary outcome (50%reduction from baseline in SESCD, CDAI, and PRO).

Primary Outcome Measures:

Simple Endoscopic Score for Crohn's Disease (SESCD), Crohn's DiseaseActivity Index (CDAI), and Patient Reported Outcome (PRO).

Inclusion Criteria:

PRO entry criteria: Abdominal pain score of 2 or more and/or stoolfrequency score of 4 or more. Primary outcome would be pain core of 0 or1 and stool frequency score of 3 or less with no worsening frombaseline. Endoscopy entry criteria: SESCD ileum only entry at score of 4and 6 if colon is involved. Primary endoscopic outcome is 40-50% deltaof mean SESCD.

Example 11: Treating Crohn's Disease (CD) in a Subject

CD is treated in a subject, by first, determining the genotypes of thesubject. Optionally, the subject is, or is susceptible to, non-responseto the induction of certain therapies such as anti-TNF, steroids, orimmunomodulators, or loses response to such therapies after a period oftime. A sample of whole blood is obtained from the subject. An assay isperformed on the sample obtained from the subject to detect a presenceof a genotype comprising at least one, but preferably three or four,polymorphism(s) provided in Table 1.

At three polymorphisms comprising rs6478109, rs56124762, and rs1892231;rs6478109, rs56124762, and rs16901748; rs6478109, rs1892231, andrs16901748; rs56124762, rs1892231, and rs16901748; rs6478109, rs2070558,and rs1892231; rs6478109, rs2070558, and rs16901748; rs6478109,rs1892231, and rs16901748; rs2070558, rs1892231, and rs16901748;rs6478109, rs2070561, and rs1892231; rs6478109, rs2070561, andrs16901748; rs6478109, rs1892231, and rs16901748; rs2070561, rs1892231,and rs16901748; rs6478109, rs7935393, and rs1892231; rs6478109,rs7935393, and rs9806914; rs6478109, rs7935393, and rs7278257;rs6478109, rs7935393, and rs2070557; rs6478109, rs1892231, andrs9806914; rs6478109, rs1892231, and rs7278257; rs6478109, rs1892231,and rs2070557; rs6478109, rs9806914, and rs7278257; rs6478109,rs9806914, and rs2070557; rs6478109, rs7278257, and rs2070557;rs7935393, rs1892231, and rs9806914; rs7935393, rs1892231, andrs7278257; rs7935393, rs1892231, and rs2070557; rs7935393, rs9806914,and rs7278257; rs7935393, rs9806914, and rs2070557; rs7935393,rs7278257, and rs2070557; rs1892231, rs9806914, and rs7278257;rs1892231, rs9806914, and rs2070557; rs1892231, rs7278257, andrs2070557; or rs9806914, rs7278257, and rs2070557, or any of the abovecombinations in which a polymorphism is substituted with a proxypolymorphism, are detected in the sample by Illumina ImmunoArray orpolymerase chain reaction (PCR) under standard hybridization conditions.Proxy polymorphisms are identified using linkage disequilibrium with aD′ value of at least 0.8, or an r² value of at least 0.85. In somecases, the proxy polymorphism is additionally selected based on anindependent association between the polymorphism and a relevant clinicalphenotype of CD (e.g., structuring and penetrating disease) In thisexample, one or more primer pairs described herein and/or nucleic acidprobes comprising nucleic acid sequences capable of hybridizing thenucleic acid sequences, or their reverse compliments, provided in SEQ IDNOS: 1-41, or 57-59, are used.

A TNFSF15 profile is generated that correlates the presence or absenceof the genotypes with a positive, negative or indeterminate result for atherapeutic response to treatment with an inhibitor of TL1A activity orexpression with a positive predictive value and specificity of at leastor about 70%.

The TNFSF15 profile of the subject is positive. Based on the TNFSF15profile of the CD patient, a doctor determines that the subject issuitable for treatment with the inhibitor of TL1A activity orexpression. A therapeutically effective amount of an inhibitor of TL1Aactivity or expression is administered to the subject with the positiveTNFSF15 profile. The inhibitor of TL1A activity or expression maycomprise an anti-TL1A antibody. The anti-TL1A antibody may be aneutralizing anti-TL1A antibody.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed:
 1. A method of treating an inflammatory, a fibrotic, ora fibrostenotic disease or condition in a subject, the method comprisingadministering to the subject a therapeutically effective amount of aninhibitor of Tumor necrosis factor-like cytokine 1A (TL1A) activity orexpression, provided at least three polymorphisms comprising rs1892231,rs56124762, rs6478109, rs2070558, rs2070561, rs11897732, rs6740739,rs17796285, rs7935393, rs12934476, rs12457255, rs2070557, rs4246905,rs10974900, rs12434976, rs16901748, rs2815844, rs889702, rs2409750,rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367,rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279,rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900,rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, orrs11221332, or a proxy polymorphism in linkage disequilibrium therewithas determined with an R² of at least 0.85, or a combination thereof, aredetected in a sample obtained from the subject.
 2. The method of claim1, wherein the at least three polymorphisms are predictive of a positivetherapeutic response in the subject to a treatment with the inhibitor ofTL1A activity or expression at a positive predictive value of at leastabout 70%.
 3. The method of claim 1, wherein the at least threepolymorphisms are predictive of positive therapeutic response in thesubject to a treatment with the inhibitor of TL1A activity or expressionwith a specificity of at least about 70%.
 4. The method of claim 1,wherein the at least three polymorphisms comprise: (a) rs6478109,rs56124762, and rs1892231; (b) rs6478109, rs56124762, and rs16901748;(c) rs6478109, rs1892231, and rs16901748; (d) rs56124762, rs1892231, andrs16901748; (e) rs6478109, rs2070558, and rs1892231; (f) rs6478109,rs2070558, and rs16901748; (g) rs6478109, rs1892231, and rs16901748; (h)rs2070558, rs1892231, and rs16901748; (i) rs6478109, rs2070561, andrs1892231; (j) rs6478109, rs2070561, and rs16901748; (k) rs6478109,rs1892231, and rs16901748; (l) rs2070561, rs1892231, and rs16901748; (m)rs6478109, rs7935393, and rs1892231; (n) rs6478109, rs7935393, andrs9806914; (o) rs6478109, rs7935393, and rs7278257; (p) rs6478109,rs7935393, and rs2070557; (q) rs6478109, rs1892231, and rs9806914; (r)rs6478109, rs1892231, and rs7278257; (s) rs6478109, rs1892231, andrs2070557; (t) rs6478109, rs9806914, and rs7278257; (u) rs6478109,rs9806914, and rs2070557; (v) rs6478109, rs7278257, and rs2070557; (w)rs7935393, rs1892231, and rs9806914; (x) rs7935393, rs1892231, andrs7278257; (y) rs7935393, rs1892231, and rs2070557; (z) rs7935393,rs9806914, and rs7278257; (aa) rs7935393, rs9806914, and rs2070557; (bb)rs7935393, rs7278257, and rs2070557; (cc) rs1892231, rs9806914, andrs7278257; (dd) rs1892231, rs9806914, and rs2070557; (ee) rs1892231,rs7278257, and rs2070557; or (ff) rs9806914, rs7278257, and rs2070557.5. The method of claim 1, wherein the at least three polymorphismsfurther comprises a fourth polymorphism comprising rs16901748,rs1892231, rs56124762, rs6478109, rs2070558, rs2070561, rs11897732,rs6740739, rs17796285, rs7935393, rs12934476, rs12457255, rs2070557,rs4246905, rs10974900, rs12434976, rs2815844, rs889702, rs2409750,rs1541020, rs4942248, rs12934476, rs12457255, rs2297437, rs41309367,rs10733509, rs10750376, rs10932456, rs1326860, rs1528663, rs951279,rs9806914, rs7935393, rs1690492, rs420726, rs7759385, rs10974900,rs1326860, rs2548147, rs2815844, rs889702, rs9806914, rs7278257, orrs11221332, or a proxy polymorphism in linkage disequilibrium therewithas determined with an R² of at least 0.85, or a combination thereof. 6.The method of method of claim 1, wherein the at least threepolymorphisms are detected in the sample by subjecting the sample to anassay configured to detect a presence of at least three nucleotidescorresponding to nucleic acid position 501 within at least three of SEQID NOS: 1-41, or 57-59.
 7. The method of claim 1, wherein theinflammatory, fibrotic, or fibrostenotic disease or condition comprisesinflammatory bowel disease, Crohn's disease, obstructive Crohn'sdisease, ulcerative colitis, intestinal fibrosis, intestinalfibrostenosis, rheumatoid arthritis, or primary sclerosing cholangitis.8. The method of claim 7, wherein the Crohn's disease is ileal,ileocolonic, or colonic Crohn's disease.
 9. The method of claim 1,wherein the subject has, or is at risk for developing, a non-response orloss-of-response to a standard therapy comprising glucocorticosteriods,anti-TNF therapy, anti-a4-b7 therapy, anti-IL12p40 therapy, or acombination thereof.
 10. The method of claim 1, wherein the inhibitor ofTL1A is an anti-TL1A antibody or antigen-binding fragment.
 11. A methodof treating an inflammatory, a fibrotic, or a fibrostenotic disease orcondition in a subject, the method comprising: (a) determining whetherthe subject with an inflammatory, a fibrotic, or a fibrostenotic diseaseor condition is suitable for treatment with an inhibitor of TL1Aactivity or expression by: (i) obtaining or having obtained a samplefrom the subject; and (ii) subjecting the sample to an assay adapted todetect at least three polymorphisms comprising rs1892231, rs56124762,rs6478109, rs2070558, rs2070561, rs11897732, rs6740739, rs17796285,rs7935393, rs12934476, rs12457255, rs2070557, rs4246905, rs10974900,rs12434976, rs16901748, rs2815844, rs889702, rs2409750, rs1541020,rs4942248, rs12934476, rs12457255, rs2297437, rs41309367, rs10733509,rs10750376, rs10932456, rs1326860, rs1528663, rs951279, rs9806914,rs7935393, rs1690492, rs420726, rs7759385, rs10974900, rs1326860,rs2548147, rs2815844, rs889702, rs9806914, rs7278257, rs11221332, or aproxy polymorphism in linkage disequilibrium therewith as determinedwith an R² of at least 0.85, or a combination thereof, and (b) treatingthe subject by administering a therapeutically effective amount of theinhibitor of TL1A activity or expression to the subject.
 12. The methodof claim 11, wherein the at least three polymorphisms are predictive ofa positive therapeutic response in the subject to a treatment with theinhibitor of TL1A activity or expression at a positive predictive valueof at least about 70%.
 13. The method of claim 11, wherein the at leastthree polymorphisms are predictive of a positive therapeutic response inthe subject to a treatment with the inhibitor of TL1A activity orexpression at a specificity of at least about 70%.
 14. The method ofclaim 11, wherein the inflammatory, fibrotic, or fibrostenotic diseaseor condition comprises inflammatory bowel disease, Crohn's disease,obstructive Crohn's disease, ulcerative colitis, intestinal fibrosis,intestinal fibrostenosis, rheumatoid arthritis, or primary sclerosingcholangitis.
 15. The method of claim 14, wherein the Crohn's disease isileal, ileocolonic, or colonic Crohn's disease.
 16. The method of claim11, wherein the wherein the inhibitor of TL1A activity or expression isan anti-TL1A antibody or antigen-binding fragment.
 17. The method ofclaim 11, wherein the at least three polymorphisms comprise: (a)rs6478109, rs56124762, and rs1892231; (b) rs6478109, rs56124762, andrs16901748; (c) rs6478109, rs1892231, and rs16901748; (d) rs56124762,rs1892231, and rs16901748; (e) rs6478109, rs2070558, and rs1892231; (f)rs6478109, rs2070558, and rs16901748; (g) rs6478109, rs1892231, andrs16901748; (h) rs2070558, rs1892231, and rs16901748; (i) rs6478109,rs2070561, and rs1892231; (j) rs6478109, rs2070561, and rs16901748; (k)rs6478109, rs1892231, and rs16901748; (l) rs2070561, rs1892231, andrs16901748; (m) rs6478109, rs7935393, and rs1892231; (n) rs6478109,rs7935393, and rs9806914; (o) rs6478109, rs7935393, and rs7278257; (p)rs6478109, rs7935393, and rs2070557; (q) rs6478109, rs1892231, andrs9806914; (r) rs6478109, rs1892231, and rs7278257; (s) rs6478109,rs1892231, and rs2070557; (t) rs6478109, rs9806914, and rs7278257; (u)rs6478109, rs9806914, and rs2070557; (v) rs6478109, rs7278257, andrs2070557; (w) rs7935393, rs1892231, and rs9806914; (x) rs7935393,rs1892231, and rs7278257; (y) rs7935393, rs1892231, and rs2070557; (z)rs7935393, rs9806914, and rs7278257; (aa) rs7935393, rs9806914, andrs2070557; (bb) rs7935393, rs7278257, and rs2070557; (cc) rs1892231,rs9806914, and rs7278257; (dd) rs1892231, rs9806914, and rs2070557; (ee)rs1892231, rs7278257, and rs2070557; or (ff) rs9806914, rs7278257, andrs2070557.
 18. The method of claim 11, wherein the at least threepolymorphisms further comprises a fourth polymorphism comprisingrs16901748, rs1892231, rs56124762, rs6478109, rs2070558, rs2070561,rs11897732, rs6740739, rs17796285, rs7935393, rs12934476, rs12457255,rs2070557, rs4246905, rs10974900, rs12434976, rs2815844, rs889702,rs2409750, rs1541020, rs4942248, rs12934476, rs12457255, rs2297437,rs41309367, rs10733509, rs10750376, rs10932456, rs1326860, rs1528663,rs951279, rs9806914, rs7935393, rs1690492, rs420726, rs7759385,rs10974900, rs1326860, rs2548147, rs2815844, rs889702, rs9806914,rs7278257, or rs11221332 or a proxy polymorphism in linkagedisequilibrium therewith as determined with an R² of at least 0.85, or acombination thereof.
 19. The method of claim 11, wherein the subject isat risk of developing a non-response or loss-of-response to a standardtherapy comprising glucocorticosteriods, anti-TNF therapy, anti-a4-b7therapy, anti-IL12p40 therapy, or a combination thereof.
 20. A method oftreating an inflammatory, a fibrotic, or a fibrostenotic disease orcondition in a subject, the method comprising administering to thesubject a therapeutically effective amount of an inhibitor of TL1Aactivity or expression, wherein the subject expresses at least threepolymorphisms comprising rs16901748, rs6478109, rs56124762, or a proxypolymorphism in linkage disequilibrium therewith as determined with anR² of at least 0.85.